Effect of low-dose esketamine on postoperative delirium in patients undergoing noncardiac surgery.

Postoperative delirium (POD) is a common and harmful complication of major
surgery in older patients and because of our
aging population growing to be a major problem. The incidence of POD varies
widely, with reported rates of 25% in
abdominal surgery and 44% to 61% in orthopedic surgery. POD is associated with
longer hospitalization, functional decline
and often results in readmission. Several etiologic factors are known to
influence the development of POD such as older
age, dementia or other cognitive disfunctionalities, systematic infection,
medication, major trauma, alcohol abuse,
anesthesia, prolonged lack of sleep, diabetes mellitus and anemia. The
different types of anesthetics given during the
course of the operation as well as the large inflammatory response induced by
surgery itself are known to have impact on
development of POD. Esketamine, a NMDA receptor antagonist, is known to induce
dissociate anesthesia. In sub anesthetic
doses it has excellent analgesic properties and favorable features like
bronchodilatory effects. A recent prospective
randomized study among cardiac surgical patients showed that a single dose of
esketamine during anesthetic induction can
reduce the incidence of POD by 90%.

Possible mechanisms of action of esketamine:
The mechanism by which esketamine reduces the incidence of POD is unknown.
Esketamine may act as a neuroprotective drug
by prevention of excitotoxic injury and apoptosis after cerebral ischemia, and
suppression of inflammatory central nervous
system responses to injury caused by surgery. Measurement of inflammation
markers is therefore warranted to examine
whether a lower incidence of POD after esketamine coincides with lower levels
of these markers in the blood. It has been
found that serum concentrations of the acute-phase inflammatory marker
C-reactive protein (CRP) was lower in esketamine treated
patients compared to those who received placebo, but these authors used a
rather insensitive method for the
determination of CRP. We propose to use a more sensitive method for evaluation
of CRP (high-sensitivity CRP) and also
determine the pro-inflammatory substances interleukin-6 (IL-6) and neopterin.
Surgery itself may increase blood levels of IL
-6 while this cytokine is also significantly elevated in cardiac surgery
patients who develop postoperative delirium. Neopterin
is produced in parallel with reactive oxygen species (ROS) by activated cells
of the immune system and this substance is
also able to enhance various effects of ROS. In humans, neopterin is therefore
considered both an indicator of the
activation of the host defense system due to trauma and a marker of oxidative
stress due to immune activation.
Esketamine has also been shown to affect the CNS cholinergic system and the
resulting release of acetylcholine may
theoretically play a role in the recovery of derangements in cerebral
concentrations of other neurotransmitters. We therefore
propose to also determine the dopamine metabolite homovanillic acid (HVA) in
our cohort. The concentration of HVA in
blood is a fairly good indicator of the changes in dopamine metabolism in the
CNS. High plasma HVA levels may reflect
increased oxidative metabolism of dopamine with the concomitant higher
production of toxic metabolites, like the oxidant
hydrogen peroxide. In an earlier study of our group, we showed that the
concentration of HVA is increased in delirious
Alzheimer*s disease patients compared to non-delirious patients. As systemic
inflammatory conditions also result in a large increase in the production of
free radicals, it is possible that both increased inflammatory processes and
high dopamine
turnover are important neurodegenerative factors that may play a role in the
pathophysiology of delirium in older patients.
Insulin-like growth factor 1 (IGF-1) has also been considered in the
pathogenesis of delirium since this neuroprotective
cytokine inhibits cytotoxic cytokines. Low IGF-1 concentrations have been
associated with the development of delirium in
acutely ill, older patients. However, other studies were inconclusive. To
investigate whether esketamine effects IGF-1
concentrations in blood and whether any changes may relate to the development
of a POD, we will also determine this
cytokine in our patient cohort.

Our main hypothesis is that
1. a single dose of esketamine reduces the incidence of postoperative delirium
in high risk patients presenting for noncardiac
surgery.

Furthermore, we hypothesize that

2. If a single dose of esketamine attenuates the incidence of postoperative
delirium, this attenuation is associated with a
decrease in the blood levels of CRP, IL-6, neopterin and HVA compared to the
placebo condition. Concerning IGF-1, we
hypothesize that the concentration of this cytokine is increased in the
intervention cohort.

Primary Objective:
In this pilot study, the authors aim is to investigate whether esketamine
reduces the incidence of POD in elderly patients
presenting for noncardiac surgery.

Secondary Objective(s):
To examine whether esketamine has an effect on the blood levels of some
biomarkers that reflect processes of inflammation,
oxidative stress and neuroprotection, and which may be associated with a
delirium.

In this double-blind, randomized, placebo controlled study we plan to study 250
patients. Patients at or above the age
of 65, who will undergo elective hip/knee replacement surgery or
major/peripheral vascular surgery under general anesthesia are eligible for
inclusion. We have chosen these types of surgery because it is shown that these
patients are at the highest risk for developing POD.
Patients will be allocated to the intervention or control group in a randomized
and double blind fashion. Group 1 will function
as the control group and these patients will receive one dose of 10 ml NaCl
0.9%. The intervention group will receive one
dose of esketamine 0.5 mg/kg dissolved in 10 ml NaCl 0.9%.

On the first, second and third day after the operation the occurance of
delirium will be assessd by means of questionnaires.

Prior to surgery and on the third day after surgery blood will be drawn for
specific biomarkers which are associated with an increased risk of
postoperative delirium.

A single dosis of esketamine 0.5 mg/kg will be given to patients allocated to
the intervention group after induction of
anesthesia.

If our hypothesis is true we will expect a lower incidence of postoperative
delirium in the intervention group. Giving a single
shot of esketamine will not create a risk for the patient. When the patient has
woken up, the blood concentration of esketamine
will be too low to induce side-effects.