COPD: Effectiveness of Therapies (2007-2008)


Creutzberg EC, Wouters EF, Mostert R, Weling-Scheepers CA, Schols AM.  Efficacy of nutritional supplementation therapy in depleted patients with chronic obstructive pulmonary disease.  Nutrition 2003;19(2):120-7.

PubMed ID: 12591542
Study Design:
Non-Randomized Controlled Trial
C - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
  • To investigate the efficacy of oral nutritional supplementation therapy in depleted patients with COPD
  • To compare the actual changes in body weight and fat free mass during nutritional supplementation with the expected, healthy body weight and fat free mass responses
  • To investigate whether oral maintenance glucocorticoid treatment could be one reason patients with COPD cannot generate anabolic responses on nutritional therapy
Inclusion Criteria:
  • COPD according to criteria of American Thoracic Society guidelines
  • FEV1 < 70% of reference value
  • Increase in FEV1 after inhalation of beta-agonist had to be less than 10%
  • Only patients in clinically stable condition were included
  • Eligibility for nutritional supplementation:  BMI no more than 21, fat free mass index no more than 15 for women, 16 for men, or BMI of no more than 25 and weight loss of at least 5% in 1 month or 10% in 6 months before admission to the pulmonary rehab center
Exclusion Criteria:
  • Concomitant confounding diseases such as malignant disorders, gastrointestinal abnormalities, recent surgery, or severe endocrine disorders were excluded
Description of Study Protocol:


Patients with COPD eligible for nutritional therapy consecutively admitted to a pulmonary rehabilitation center.

Design:  Nonrandomized Clinical Trial with Historical Controls 

Blinding used (if applicable):  not applicable 

Intervention (if applicable)

  • Two to three oral liquid nutritional supplements (2812 +/- 523 kJ/day, 61% carbohydrate, 19% fat, 20% protein) incorporated into an 8-week inpatient pulmonary rehabilitation program including physical training

Statistical Analysis

Changes between groups between baseline and 8 weeks were tested by applying Student's paired t test for dependent samples.  Bonferroni's correction was applied to correct for multiple comparisons.  Differences in baseline parameters between users and non-users of oral glucocorticoids were analyzed with Student's t test for independent samples when variables were normally distributed.  Mann-Whitney U test was applied for non-normally distributed variables.  Differences in the response to nutritional supplementation after 8 weeks betwen users and non-users of oral glucocorticoids were tested with ANOVA.

Data Collection Summary:

Timing of Measurements

Measurements taken before and after 8 weeks of intervention.

Dependent Variables

  • FEV1 and inspiratory vital capacity calculated from flow volume curve with spirometry
  • Arterial oxygen and carbon dioxide tension analyzed on blood gas analyzer
  • Resting energy expenditure through indirect calorimetry
  • Body weight, height, BMI
  • Body composition and fat-free mass by bioelectrical impedance analysis
  • Respiratory muscle function measured through maximal inspiratory mouth pressure
  • Peripheral muscle function measured through handgrip strength
  • Exercise performance measured by 12 minute walk and in a subgroup of 38 subjects, by incremental bicycle ergometry
  • Disease-specific health status measured by St. George's Respiratory Questionnaire
  • Well-being assessed by the Medical Psychological Questionnaire for Chronic Lung Patients
  • Blood samples analyzed for serum protein, albumin and C-reactive protein

Independent Variables

  • Two to three oral liquid nutritional supplements (2812 +/- 523 kJ/day) incorporated into an 8-week inpatient pulmonary rehabilitation program including physical training
  • Unselected subgroup of 48 patients asked to register their food intakes over 4 consecutive days

Control Variables

  • Sex
  • Age
  • Height
  • Body composition
  • Dietary intake
Description of Actual Data Sample:

Initial N: 64 patients with COPD (49 men, 15 women); 28 historical controls (21 men, 7 women)

Attrition (final N):  64 subjects, 28 historical controls

Age:  non-users of glucocorticosteroids:  62 +/- 10 years, users:  67 +/- 6 years

Ethnicity: not mentioned

Other relevant demographics:  48% of patients were treated with low-dose oral glucocorticosteroids as maintenance medication (dose equivalent to 7.6 +/- 2.5 mg of methylprednisolone per day).

Anthropometrics:  No significant differences between groups except for arterial O2 pressure (p < 0.05) and fat free mass index (p < 0.05).

Location:  The Netherlands


Summary of Results:




8 weeks

Pre-post P

Dietary Intake (kJ/day) 9,690 +/- 2,184 11,523 +/- 2,330 <0.001

Dietary intake/REE

1.6 +/- 0.4

1.9 +/- 0.3


Protein intake/body weight (g/kg/day) 1.6 +/- 0.4 1.9 +/- 0.4 <0.001
Protein intake (%) 16 +/- 2 17 +/- 2 0.013
Carbohydrate intake (%) 45 +/- 6 49 +/- 5 <0.001
Fat intake (%) 39 +/- 5 35 +/- 4 <0.001
Body weight (kg) 57.4 +/- 7.0 59.5 +/- 7.1 <0.001
Fat free mass (kg) 43.6 +/- 6.0 44.7 +/- 6.0 <0.001
Serum protein (g/L) 63.2 +/- 5.8 66.0 +/- 5.2 <0.001
Serum albumin (g/L) 43.9 +/- 3.8 44.8 +/- 3.1 NS
Maximum inspiratory mouth pressure (cm H2O) 70 +/- 19 74 +/- 18 0.001
Handgrip strength (kg) 31.9 +/- 7.8 33.1 +/- 8.2 0.004
12-minute walking distance (m) 708 +/- 181 840 +/- 204 <0.001
Peak work load (W) 53 +/- 20 59 +/- 24 0.001
Peak lactate/peak work load (mM/W*l) 0.07 +/- 0.03 0.06 +/- 0.02 0.037
Peak oxygen consumption (mL/min) 833 +/- 195 884 +/- 257 0.041
Peak oxygen pulse (mL) 7.0 +/- 1.8 7.5 +/- 2.2 0.020
SGRQ - Symptom score (points) 55 +/- 20 46 +/- 21 <0.001
SGRQ - Activity score (points) 65 +/- 22 66 +/- 20 NS
SGRQ - Impact score (points) 41 +/- 19 37 +/- 17 0.043 
SGRQ - Total score (points) 50 +/- 17 47 +/- 16 NS
SGRQ - Subjective health perception (mm) 53 +/- 17 58 +/- 16 0.033
MPQC - Well-being (points) 23 +/- 8 26 +/- 8 0.016
MPQC - Invalidity (points) 30 +/- 3 29 +/- 4 NS
MPQC - Displeasure (points) 7 +/- 3 6 +/- 3 NS

MPQC - Social inhibition (points)

13 +/- 4

13 +/- 3


Other Findings

Increases in body weight (2.1 +/- 2.1 kg, P < 0.001) and fat-free mass (1.1 +/- 2.0 kg, P < 0.001) were seen.

Further, maximal inspiratory mouth pressure (4 +/- 10 cm of H20, P = 0.001), handgrip strength (1.2 +/- 3.1 kg, P = 0.004), and peak workload (7 +/- 11 W, P = 0.001) significantly improved.

Clinically significant improvements in tbe items symptoms (9 +/- 16 points, P < 0.001) and impact (4 +/- 15 points, P = 0.043) of the St. George's Respiratory Questionnaire were achieved.

Oral glucocorticosteroid treatment significantly impaired the response to nutritional supplementation therapy with respect to maximal inspiratory mouth pressure, peak workload, and St. George's Respiratory Questionnaire symptom score.


Author Conclusion:
In conclusion, nutritional supplementation therapy with an 8-week inpatient pulmonary rehabilitation program improved body composition, respiratory and peripheral muscle function, exercise capacity, and health status in our group of depleted or weight-losing patients with COPD.  The use of long-term, low-dose oral glucocorticosteroids as maintenance anti-inflammatory medication significantly impaired patients' response to nutritional supplementation with respect to respiratory muscle function, exercise capacity, and health status.  Because this study provided further evidence for the adverse side effects of systematic glucocorticosteroids, clinicians should carefully consider the prescription of oral glucocorticosteroids as maintenance medications in COPD.
Funding Source:
Reviewer Comments:
Subjects and controls taken from different studies.  Significant differences between groups at baseline.  Not all measurements made in all subjects.
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? N/A
  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? ???
  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? ???
3. Were study groups comparable? No
  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? No
  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? N/A
  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? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  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.) Yes
  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? N/A
  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? ???
  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? ???
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)? N/A
  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? N/A
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? Yes