Outcome parameters will be measured after inclusion and at three months after discharge.
Primary outcome is change in activities of daily living, determined as functional limitations and physical activities. All outcome parameters that will be measured are listed below.
Activities of daily living
Activities of daily living (ADL) will be assessed with a validated questionnaire that measures the degree of difficulties patients experience with six activities: climbing stairs, walking 5 minutes outdoors without resting, getting up and sitting down in a chair, dressing and undressing oneself, using own or public transportation, and cutting one's own toenails . Functional limitations will be assessed using five difficulty categories, ranging from "No I can not' to 'Yes without difficulty'. Total score will be calculated by summing the scores of all activities, ranging from 0 (does not have any difficulties with the activities) to 6 (has difficulties with all activities).
The performance test of physical function includes time measures of walking speed, rising from a chair, putting on and taking off a cardigan, and maintaining balance in a tandem stand [21–23]. To test walking performance a 3 meter walking course is created by a measuring line. Patients are instructed to walk to the other end of the course, to turn 180 degrees, and walk back as quickly as possible. Patients are allowed to use a walking aid if necessary. To test the ability to rise from a chair, patients are asked to fold their arms across their chest and to stand up and sit down five times from a standard hospital chair as quickly as possible. For the cardigan test, patients are asked to put on and take off a cardigan as quickly as possible. To test for balance, patients are asked to stand with one foot placed behind the other in a straight line for at least 10 seconds.
A trained research assistant records the total time needed to complete each test.
Patients who complete the walking test, chair test and cardigan test will be assigned scores between 1 and 4, corresponding to the quartiles of time needed to complete the test, with the fastest time scored as 4. Those who cannot complete the test will be assigned a score of 0. Accordingly the maximum score for these three tests ranges from 0-12 points, after adding up the result of these tree tests.
The balance test will be analyzed separately, yet with the same time classification as described above.
Physical activity will be assessed with the validated LASA Physical Activity Questionnaire (LAPAQ) . This face-to-face questionnaire covers the frequency and duration of walking outside, cycling, gardening, sports and household activities during the previous two weeks. Walking and bicycling for transportation purposes are considered as common daily activities in The Netherlands, and not as sports activities. For the analyses, the total time spent on physical activity of the last two weeks is used (in minutes per day).
Quality of life
Quality of Life will be measured by the SF-12 and EuroQol (EQ-5D and EQ-VAS).
The SF-12 contains 12 questions from the SF-36 . These questions concern functional status -both physical and social functioning-mental health, pain, vitality and evaluation of persons' state of health. With these dimensions two total scores can be calculated; one physical component score and one mental component score .
EuroQol (EQ-5D) is a standardised instrument to monitor health outcome . This instrument contains five short questions on mobility, self-care, daily activities, pain/discomfort and anxiety/depression with three possible response categories (no problems, moderate problems, severe problems). The EQ-5D scores were used to calculate utilities using the Dutch tariff . QALYs were calculated by multiplying the utilities with the amount of time a patient spent in a particular health state. Transitions between health states were linearly interpolated.
Additionally we will administer the EQ VAS. The EQ-VAS, a visual analog scale, generates a self-rating of health-related quality of life. The patient rates his/her health state by drawing a line from the box marked "Your health state today" to the appropriate point on the EQ-VAS on a scale of 0 to 100.
Hand grip strength
Hand grip strength (in kg) will be measured with a hydraulic hand dynamometer (Baseline, Fabrication Enterprises Inc., Elmsford, NY, USA). Respondents are asked to perform two maximum force trials with their non-dominant hand. The highest value will be used. Measured data will be compared to reference values by Mathiowetz. Data will be expressed as percentage of reference value .
Patients will be asked to report all fall incidents weekly in a fall diary for a period of three months after discharge. A fall is defined as "an unintentional change in position resulting in coming to rest at a lower level or on the ground" .
Bio-electrical impedance spectroscopy
Bio-electrical impedance spectroscopy (BIS) will be applied to calculate (changes in) body composition. Measurements will be performed at the non-dominant side of the patient, using a Hydra ECF/ICF Bio Impedance Spectrum Analyzer, model 4200 (Xitron Technologies, San Diego, CA, USA). Shoes, socks and jewellery will be removed and patients will be in supine position. Two current electrodes (tetra-polar electrodes (3 M red Dot AG/AgCl)) will be placed at the dorsal surfaces of the hand and foot on the distal position of the second metacarpal and metatarsal, respectively. Two detector electrodes will be placed at the posterior wrist between the styloid processes of the radius and ulna and at the ankle between the tibial and fibular malleoli. With this technique, two body compartments, fat mass (FM) and fat free mass (FFM), can be determined. Patients with a pacemaker will be excluded from this measurement.
Resting energy expenditure
Resting energy expenditure (REE) will be calculated from measurements of oxygen consumption (VO2) and carbon dioxide production (VCO2) by with a ventilated hood system, in supine position for 30 minutes, with a metabolic monitor (Vmax Encore n29, Viasys Healthcare, Houten, The Netherlands). Before each measurement, gas analyzers will be calibrated with two reference gas mixtures (a. 16% O2, 4% CO2, bal. N2 and b. 26% O2, bal. N2. (Viasys)). Patients will be monitored during the measurement to prevent movements or sleeping under the hood.
REE will be calculated from oxygen consumption and carbon dioxide production by using the equation of Weir .
Dietary intake will be obtained by asking in broad outlines for patients' mean daily intake of food and drinks in the two weeks before admission to the hospital and at three months after discharge.
Biochemical parameters CRP, IGF-1, 25(OH)D
Two blood samples per patient will be obtained: the first on the day after inclusion and the second three months after discharge. We will measure CRP, IGF-1 and 25(OH)D in both samples. The blood samples will be centrifuged and stored at -80°C. All blood samples will be analyzed simultaneously after completing full data collection.
C-reactive proteïn (CRP in mg/l) is a member of the class of acute-phase reactants as its levels rise dramatically during inflammation processes. Plasma concentrations of C-Reactive Protein (CRP) will be measured with an automated latex-enhanced immunoturbidimetric assay on a Modular P800 analyzer (Roche Diagnostics, Almere, The Netherlands).
Insuline-like growth factor (IGF-1 in μg/l) will be obtained to observe over or under production of growth-hormone. Serum levels of IGF-1 will be measured with a Immulite 2500 analyzer (Siemens, Deerfield, IL, USA)
Serum 25(OH)D (in nmol/l) will be obtained to observe differences in vitamin D levels after the three month supplementation of vitamin D in the intervention group. This will be determined using a competitive protein binding assay (Nichols Diagnostics, San Juan Capistrano, CA, USA).
All analyses will be performed at department of Clinical Chemistry of the VU University Medical Center.
Costs will be measured from a societal perspective. Direct health care costs include the costs of transmural nutritional support (nutritional supplements plus dietitian), hospitalization, additional visits to other health care providers (general practitioner, medical specialist), prescription and over-the-counter medication, professional home care. Direct non-health care costs of paid and unpaid help and indirect cost of absenteeism of paid and unpaid work will also be included.
Data on the use of nutritional support will be registered by the dietician implementing the transmural nutritional intervention. Data on health care utilization during hospitalization will be retrieved from medical records and the hospital information system. Use of other health care resources after discharge from the hospital will be collected through two identical cost diaries each spanning a period of 6 weeks. Medication data will be obtained from the patients' pharmacies.
Health care utilization will be valued using standard costs from the Dutch guidelines for cost analysis in health care research . If there are no standard costs available, tariffs or prices from health care providers themselves or professional organizations will be used. The costs of medication will be estimated on the basis of prices charged by the Royal Dutch Society for Pharmacy.
The aim of the economic evaluation will be to determine and compare the total costs for patients receiving either transmural nutritional support or usual care, and to relate these costs to the effects of the interventions.
Incremental cost-effectiveness ratios (ICERs) will be calculated by dividing the difference in mean total costs between the two interventions by the difference in mean effects between the two interventions. The ICERs will be calculated for the primary clinical effect measures of the trial, i.e. functional status and ADL. Cost-utility ratios will also be calculated.
Bootstrapping will be used for pair-wise comparison of the mean differences in total costs between the intervention groups. Confidence intervals will be obtained by bias corrected and accelerated (Bca) bootstrapping using 5000 replications . To estimate the uncertainty surrounding the ICERs bias corrected accelerated bootstrapping (5000 replications) will be used. The bootstrapped cost-effect pairs will be plotted on cost-effectiveness planes and will be used to estimate cost-effectiveness acceptability curves.