Neurotoxic changes in cerebral glucose metabolism during anaesthesia and major surgery; is the polyol pathway activated?

Anaesthesia is very effective in facilitating surgery, which is illustrated by
over 1.4 millions of procedures performed each year in The Netherlands alone.
However, postoperative cognitive dysfunction (POCD) is present in up to 8 out
of 10 patients, depending on patient age, comorbidities and type of surgery.
This has a major impact on quality of life and capability of returning to work
after a procedure and the underlying pathophysiology needs to be interrogated
to be able to develop proper treatment. POCD has been reported in relation to
hypoglycemia. It is also suggested to be associated with hyperglycemia,
although this is less constantly reported.

Along with the intended depression of the state of consciousness, anaesthetic
drugs also decrease the cerebral glucose metabolism by 25-63%. Paradoxically,
plasma glucose increases during surgery, due to the surgical stress response.
This so called *stress hyperglycaemia* results from activation of the
hypothalamic-pituitary-adrenal axis during surgery. We have shown that even
with minor surgery, plasma glucose will increase depending on the length of the
procedure. According to the Michaelis-Menten equation, the glucose content of
the brain depends on glucose supply (from blood stream) and facilitated
transport by the GLUT-1 transporter. An increase in blood plasma glucose will
thus cause and increase of glucose in the brain. The combination of decreased
glucose metabolism and increased plasma glucose will lead to an excess cerebral
glucose supply and demand mismatch during general anaesthesia and surgery.

From studies in patients with diabetes mellitus we know that during chronic
hyperglycaemia the normal phosphorylation of glucose via the hexokinase pathway
will become saturated and the excess of glucose is processed via the polyol
pathway. In this pathway, glucose is metabolized by aldose reductase to
sorbitol and fructose. Sorbitol is a hydrophilic alcohol that does not diffuse
easily across cell membranes and therefor has osmotic potential. In addition,
the formation of sorbitol reduces the capability of the cells to protect
against influences of reactive oxygen species. Finally, fructose is capable of
irreversibly glycating and damaging proteins, forming advanced glycation end
products (AGEs). All cited effects are by itself cytotoxic and thus neurotoxic
mechanisms. Evidence on activation of the polyol pathway in the brain is
scarce, most likely because it is only possible to measure the metabolites in
the cerebrospinal fluid, which is not readily accessible for frequent sampling.

It has been proven to be challenging to study the metabolism of the brain; this
includes the anaesthetized patient. As a consequence, there are no data on
changes in cerebral metabolism in the perioperative period and anaesthesia and
its effect on the brain*s metabolism are still considered a *mystery*.

We will study the cerebral glucose metabolism before, during and after surgery
by sampling the cerebrospinal fluid (CSF) via the spinal catheter in patients
undergoing thoracic surgery. Changes in cerebral glucose metabolism and
activation of the polyol pathway (sorbitol and fructose) will be determined to
test the hypothesis.

We will perform an observational single center cohort study in the Netherlands
with an expected duration of 2 years. The study will be conducted at the
Amsterdam UMC, location Amsterdam.

The burden to the patient is considered to be low. The collection of general
data from (electronic) medical records does not affect the patients. Blood
sampling will be combined with routine sampling for standard care of thoracic
aorta surgery patients where possible. The artery line that*s already present
shall be used. The liquor sampling will be done from the reservoir which is
placed as part of standard care. The liquor in this reservoir can be viewed as
residual material.

CSF sampling: a lumbar drain is placed routinely according to standard work
protocol the day before surgery under local anaesthesia and aseptic conditions.
A fasting plasma glucose is determined. We will collect the first CSF sample
from the reservoir 15 minutes before induction of anaesthesia (t=-15 min), when
the patient has had an overnight fast. The second samples are collected before
the start of cardiopulmonary bypass and the third samples will be collected
after stopping cardiopulmonary bypass. After discharge from the operating
theatre, samples will be taken every morning before breakfast (i.e. fasting)
until removal of the catheter, at latest 48 hours after surgery. We will
collect 2 ml of CSF from the reservoir at every measurement point in
polypropylene tubes. An estimated 4-5 repeated paired measurements per patient
would be collected.

Blood sampling: when a CSF sample is obtained, a paired plasma sample will be
collected from the arterial line that all patients receive before surgery as
part of routine clinical care. In this sample, cortisol and CRP will also be
measured.

Cerebral perfusion measurement: we will assess the change of cerebral perfusion
using transcranial Doppler monitoring. This measurement device will be placed
when the patient is under anesthesia and shall be removed before the patient
awakes.

Neurocognitive function test: in all participating subjects, we will administer
a questionnaire to assess pre- and postoperative cognitive dysfunction, as
measured by the Montreal Cognitive Assessment (MoCA). The questionnaire is
administered the day before surgery and 2 weeks after surgery.

This study could aid our understanding in the interaction of blood and liquor
glucose levels during major surgery and how their metabolism could play a part
in the development of postoperative cognitive dysfunction.