Preoperative home-based multimodal prehabilitation in patients scheduled for liver or pancreatic resection

The morbidity rates after resection of hepatic and pancreatic tumours are high.
Older patients, especially the frail patients, are more prone to complications
and require specific preoperative risk stratification. The anaerobic threshold
(AT), assessed by cardiopulmonary exercise testing (CPET), can be used to
identify high risk patients. Preoperative exercise prehabilitation can improve
the physical condition of older patients before intra-abdominal surgery. There
is limited evidence regarding the improvement of physical fitness after
exercise prehabilitation in patients undergoing liver or pancreatic resection,
and the feasibility of a prehabilitation program in these patients. Moreover,
to enhance the anabolic effect of physical training, improve lean body mass and
obtain or maintain an optimal nutritional status during the prehabilitation
period, sufficient intake of nutrients is required. We hypothesize that
multimodal prehabilitation (exercise program and nutritional supplements) will
improve the preoperative anaerobic threshold, we assume to reach an average
increase of 1.5 ml/kg/min, in patients with a low cardiorespiratory reserve
(anaerobic threshold <11 ml/kg/min) undergoing elective liver or pancreatic
resection.

The primary objective is to assess the (preliminary) effectiveness of a 4-week
home-based exercise training program on an advanced cycle ergometer and the
administration of nutritional supplements on preoperative aerobic capacity as
measured by the anaerobic threshold in high-risk patients (anaerobic threshold
<11 ml/kg/min) scheduled for elective liver or pancreatic resection. Secondary
outcome measures include to assess the feasibility (adherence, adverse events,
motivation, patient appreciation) of the 4-week home-based multimodal program,
changes in other preoperative CPET measures, changes in preoperative quality of
life score, effect of prehabilitation on the immune system by assessing
biomarkers, individual changes in physical fitness and daily physical activity
during the prehabilitation program, and skeletal muscle metabolic function
(energy metabolism). Data on operative intervention, perioperative outcomes and
postoperative progress will also be collected.

This study is a multicenter study with a pre- en posttest design. It will run
from December 2017 until all patients are included, this will probably be in
June 2020. The study will take place in Medisch Spectrum Twente in Enschede,
Universitair Medisch Centrum Groningen and Maxima Medisch Centrum. If informed
consent is obtained from eligible candidates they will all receive the
prehabilitation program before surgery. A small subgroup will be asked to
perform a second, in-magnet, exercise test at various exercise intensities
using a MR-compatible ergometer 1-2 days after the first and second CPET.

Twenty-four patients will receive four weeks (12 sessions in total) of partly
supervised home-based exercise training before surgery. An advanced cycle
ergometer (Lode Corival, Lode BV, Groningen, the Netherlands) will be delivered
at the patients* home. The training program, two sessions a week of interval
training and one session a week of endurance training, twice combined with
periphery muscle training, will be personalized to candidates. The
physiotherapist will visit the patient three times a week in the first week,
and once a week in week 2-4. Patients group will receive protein
supplementation immediately following exercise and (± 30 minutes) before sleep,
providing a standard dosage of 30 g of a high-quality (whey and casein) protein
that contains at least 10 g of EAA, of which 2-3 g leucine. Moreover, patients
will daily receive vitamin D and a multivitamin/mineral supplement. After the
first CPET and prior to the second CPET blood samples will be collected, and
interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP), and tumor necrosis
factor (TNF)-* will be measured. In a small subgroup (n=5), an additional,
in-magnet, exercise test using an MR-compatible ergometer will be performed one
or two days after each regular CPET to evaluate the effects of the
prehabilitation program on skeletal muscle metabolic function (energy
metabolism).

The risks associated with participation in this study are considered slightly
increased, because the training program is partly unsupervised. But before the
start of the training program a CPET will be performed under controlled
condition under the guidance of trained employees to assess baseline
cardiorespiratory fitness, as well as to examine whether or not there are
contraindications for physical exercise training (safety). The prehabilitation
program will be personalized to each patient based on individual steep ramp
test results. The training program itself will be executed at a submaximal
exercise intensity. We think the slightly increased risk is justified because
of the expectation that the intervention will lead to better fitness and
subsequently to better outcomes.