A randomized controlled trial on the effect of beetroot juice on VO2max in patients undergoing a minimally invasive esophagectomy

The cornerstone for curative treatment of esophageal cancer is an esophagectomy
and with the introduction of neoadjuvant chemoradiotherapy, the survival rate
for patients undergoing surgery has significantly improved over the past
decades. However, an esophagectomy is a technically challenging procedure that
requires sufficient amount of surgeon volume to progress through the learning
curve, in addition to the intensive treatment associated with a high
postoperative morbidity. Despite improvements in perioperative care, such as
introduction of enhanced recovery after surgery programs (ERAS) and minimally
invasive surgery, postoperative morbidity following an esophagectomy remains
substantial. More specifically, the cardiopulmonary complication rate remains
around 52% (own data).
In this light, prehabilitation has gained increasing attention. Prehabilitation
consists of various interventions to optimize the patient*s preoperative
physical and mental state. Improvement of a patient*s fitness should lead to a
better functional capacity that allows patients to better withstand the
postoperative stress response by increasing the maximum oxygen uptake (VO2max).
In major abdominal surgery, multiple studies have indicated that
prehabilitation not only improves preoperative functional capacity but that it
also has a beneficial effect on short-term outcomes. In patients undergoing an
esophagectomy, evidence on the effectivity of prehabilitation is scarce,
however, it has been reported that patients with lower VO2max and VO2peak (the
peak oxygen uptake during incremental exercise) values have a significantly
higher risk of cardiopulmonary complications (CPC) following an esophagectomy.
In sports medicine, multiple studies have shown that BRJ supplementation
increases VO2max and thereby improves exercise performance and oxygen
metabolism in both young, healthy individuals as well as the elderly suffering
from cardiovascular disease and COPD. BRJ supplementation increases time to
exhaustion during high-intensity exercise and reduces oxygen consumption (VO2)
during submaximal exercise via release of Nitric Oxide (NO). BRJ contains an
abundant amount of nitrate and it is thought that VO2max may be increased via
NO-mediated changes in local perfusion in skeletal muscle and possible effects
on cardiac output. However, the exact mechanisms remain unclear and most of
these studies are limited by a small study population and effect size. Positive
effects of BRJ supplementation are mostly described when BRJ is taken at least
one consecutive week of daily dosing rather than one single dose.

The primary aim of this study is to investigate the added effect of one
consecutive week of BRJ consumption on VO2max in prehabilitated patients
scheduled to undergo a minimally invasive esophagectomy for cancer.

This study will be a single center, double-blind, randomized,
placebo-controlled trial. The Catharina Hospital Eindhoven, the Netherlands -
which is a tertiary referral center for esophageal cancer - is the only Dutch
hospital with a prehabilitation program (PREPARE) installed for patients
scheduled to undergo an esophagectomy.

The intervention group will receive the Beet It Sport Shot - manufactured by
James White Drinks (Ipswich, UK) - containing 400 mg (~6.5 mmol) nitrate per
bottle of 70 millilitres, to take once daily for seven days prior to surgery.
The control group (placebo) will receive an identical (blinded) bottle of the
Beet It Sport Shot of 70 millilitres in which the nitrate has been removed by
the manufacturer, to also take once daily for seven days
prior to surgery.

BRJ consumption has not yet been investigated in this population. However,
previous and similarly designed trials in various study populations did not
report serious adverse events or major health consequences from BRJ consumption
and showed a good tolerance of the supplementation regimen. BRJ supplementation
is commercially available and approved for consumption. Thus, we expect no
additional events or complications caused by BRJ consumption in this trial
compared to previous trials. Measurements will be part of the standard clinical
care pathway installed at the hospital