A randomised, single blinded, prospective, observational study of molecular biological effects of xenon inhalation used for early preconditioning in humans undergoing coronary artery bypass grafting

Ischaemic preconditioning describes the protection of myocardial tissue against
infarction by short, non-lethal periods of ischaemia. In the last years the
volatile anaesthetics, like e.g. isoflurane, have been recognized to mimic the
strong cardio protection exerted by ischaemic preconditioning (pharmacological
or anaesthetic induced preconditioning). Recent data indicate that also the
inert gas xenon is able to induce preconditioning of the heart in vivo. Xenon
inhalation resulted in a significant reduction of the infarct size compared
with controls. Calphostin C, an inhibitor of protein kinase C (PKC), and the
p38 mitogen activated protein kinase (MAPK) inhibitor SB203580 abolished the
preconditioning effects of xenon and isoflurane. These data suggest that PKC
and p38 MAPK are key mediators of xenon-induced preconditioning. PKC-epsilon
(PKC-e) is one of the isoforms present in cardiac myocytes and is mainly
implicated in preconditioning mechanisms. Activation of PKC affects other
downstream signalling pathways like the MAPK cascade, and in this context it
has been shown that PKC-e interacts with MAPK during cardio protection. Xenon
induced a significant increase of p38 MAPK phosphorylation and calphostin C
abrogated this effect, demonstrating that p38 MAPK is located downstream of PKC
in the signalling cascade of xenon-induced preconditioning.
These data show that xenon induces cardio protection by preconditioning and
that activation of PKC-e and its downstream target p38 MAPK are central
molecular mechanisms involved. Xenon activates MAPKAPK-2 and HSP-27 downstream
of PKC and p38 MAPK and these data link preconditioning by xenon to the actin
cytoskeleton. Although these data suggest some steps of the signal transduction
cascade, the end-effectors of preconditioning mediating the cardio protective
effect remains to be elucidated.
The present application seeks to investigate whether the identified enzymes of
xenon-induced preconditioning play a role in a clinical setting of myocardial
ischaemia. Xenon should be given shortly before aortic cross clamping in
patients scheduled for coronary artery bypass surgery. Protein modifications
should be correlated to clinical cardio-protective effects of xenon measured by
troponin T and pro-BNP levels. To investigate whether clinical neuro-protective
effects may occur at the same time, also the level of S-100 protein will be
measured and patients will be asked to fill in neuro-cognitive questionnaires.

The aim of this study is to evaluate cardio-protective effects of xenon
inhalation in humans and to identify enzymes contributing to cardio-protection
influenced by xenon in patients scheduled for CABG surgery.

This study is designed as a randomised single blinded prospective observational
study. In this combined clinical-laboratory investigation with collaboration
between the Thorax centre of ErasmusMC, Rotterdam and the Laboratory of
Experimental Intensive Care and Anaesthesiology (LEICA) of Academic Medical
Centre, Amsterdam, a total number of 20 patients per group, giving 60 patients
totally will be enrolled.

Group A will receive in a 1 block period of 15-min: 65% xenon together with
35% oxygen,
Groep B will receive in 3 blocks of 5-min per block with an intercept of 5 min
between the blocks: 65% xenon together with 35% oxygen,
Groep C will receive a 1 block period of > 10-min of 100% oxygen.

non applicable