Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04966247 |
| Other study ID # |
299015 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2023 |
| Est. completion date |
August 31, 2024 |
Study information
| Verified date |
February 2024 |
| Source |
Barts & The London NHS Trust |
| Contact |
Myat Soe Thet, MD, MSc |
| Phone |
+44 20 7377 7000 |
| Email |
myatsoe.thet[@]nhs.net |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Aortic arch repair surgery is a technically complex and challenging procedure to treat aortic
pathologies. Despite advancements in perioperative care, detrimental neurological
complications occur during or after surgery. The neurological complications increase the
economic burden of healthcare, morbidity and quality of life for the patients, even if they
survive. Stroke, for example, leads to an increase in healthcare and social care costs,
requiring a subsequent lengthy rehabilitation. Milder neurological impairments include
transient ischaemic attacks, confusion and delirium, necessitating longer intensive care and
hospital stay.
Currently applied cerebral monitoring modalities are electroencephalogram and cerebral
oximetry. However, they are not specific enough to timely detect early cerebral ischaemia to
prevent neurological complications. S100B protein and neuron-specific enolase are serum
markers that reflect cerebral damage, however, their applicability in the hyperacute setting
is limited. However, rapid measurements of glial fibrillary protein have paved new pathways
to detect cerebral injury. Recent studies reveal more sensitive biomarkers of glucose,
lactate, pyruvate, glutamate and glycerol. These biomarkers could potentially detect cerebral
ischaemia on a near real-time basis using the microdialysis method. The aim of the project is
to develop a bedside system for early detection of cerebral ischaemia on a near real-time
basis during aortic arch surgery.
Early detection of cerebral ischaemia could mandate more aggressive cerebral protection
strategies by further optimisation of hypothermia and antegrade selective cerebral perfusion
during surgery, and optimisation of blood pressure and oxygenation in the intensive care
unit. Ultimately, early detection of cerebral ischemia during surgery will prevent disabling
and costly neurological complications following surgery.
Description:
Aortic arch surgery is used to treat life-threatening aortic dissections, aortic aneurysms
involving the arch and other aortic pathologies. The procedure is performed under deep
hypothermic circulatory arrest. Neurological complications are detrimental and disabling for
the patients, even if they survive. In the 1990s, the risk of stroke after aortic arch
surgery was 48% with deep hypothermic circulatory arrest. The risk of stroke has largely
decreased to about 3% after elective surgery and 11% after emergency aortic arch repair in
recent years, largely attributed to the development of current cerebral protection
strategies. Despite this, the risk of stroke is considerably high and it accompanies
devastating disabilities for the patients leading to longer hospital stays and lower quality
of life for surviving patients.
Neurological complications are not without an economic burden on the NHS healthcare system.
After analysing 84,184 patients admitted to hospital with a stroke, it is reported that the
mean total healthcare and social care cost of a stroke patient in the UK is £22,429 at 1
year, and this amount increases to £46,039 in 5-year. The costs also increase with age and
severity of the stroke (Figure 1).
Electroencephalogram (EEG) and cerebral oximetry are currently used modalities for cerebral
ischaemia monitoring, yet, they fail to detect early cerebral ischaemia. EEG only processes
data from superficial cortex areas only. It is also affected by anaesthetic agents,
neuromuscular blocking agents and other intraoperative factors. Cerebral oximetry uses
near-infrared spectroscopy (NIRS) to monitor cerebral regional oxygen saturation in the
frontal cortex. It has a weak predictive value of neurological events, and no data exists to
support the optimum threshold of oximetry. Moreover, there is no association between
spectroscopy measurements and stroke. The latest emerging imaging modality for monitoring is
transcranial doppler ultrasound. It is operator-dependent and images are usually acquired
through a small transtemporal window. It measures velocity in cranial arteries such as middle
cerebral arteries, and it is still yet to be validated with larger studies. Limitations in
these monitoring modalities could often bring the adequacy of cerebral protection into
question.
The brain is a very sensitive organ to hypoxemia, and mixed venous oxygen saturation can be
used to estimate the oxygen delivery and usage in the body by measuring the blood returning
to the right side of the heart. Mixed venous saturation is influenced by many factors, such
as cardiac output, respiration and oxygenation, and tissue metabolism in the perioperative
period. Intraoperatively, it could serve as a more specific marker of global oxygen delivery
during the cardiopulmonary bypass since the pump flow and metabolic rates are fairly
constant.
Alternatively, certain proteins, such as the S100B protein, neuron-specific enolase and glial
fibrillary protein (GFAP) could be monitored. They are released into the cerebrospinal fluid
(CSF) and blood after cerebral damage. Their concentrations correlate with the extent of
cerebral injury and predict the adverse clinical outcomes. However, S100B and neuron-specific
enolase cannot accurately diagnose stroke, even after 6 hours from the onset of clinical
symptoms. Moreover, their measurement results could take at least 2 hours, and also
reliability of the measurements decrease with the use of cardiopulmonary bypass. Hence, their
applicability in the hyperacute setting of aortic surgery is very limited.
On the other hand, GFAP and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have been
described as emerging biomarkers for cerebral injury in an acute setting. The conventional
measurement of GFAP using ELISA assays cannot reliably detect low levels of GFAP, especially
in the blood. However, since the introduction of the portable point-of-care device to measure
GFAP and UCH-L1 levels in the blood, these could be measured in as little as 10-15 minutes.
This has paved the way for further exploring the role of GFAP as a biomarker for the early
identification of cerebral ischaemia in aortic arch surgery.
Recent studies have evaluated the role of metabolic biomarkers; glucose, pyruvate, lactate,
glutamate, and glycerol, in cardiac surgery, using the microdialysis method. Although
conventional analysis of biomarkers is difficult on a near real-time basis, it is feasible
using the microdialysis method. It has been validated and in clinical use for more than 30
years. The microdialysis system consists of a small catheter with a semipermeable membrane
placed in the interstitial space and physiologic salt solution is constantly perfused in the
catheter allowing some of the solutes to diffuse from the interstitial space into the
microdialysis catheter along a concentration gradient. The dialysate can then be analysed for
concentrations of biomarkers.
Choice of biomarkers (glucose, pyruvate, lactate, glutamate, and glycerol) is largely
dependent on the commercially available analysis capacity of microdialysis method and
previous studies on biomarkers in cardiac surgery. Glucose is the sole fuel of the brain. It
is broken down in the glycolytic pathway to generate pyruvate, which is then used in
mitochondria by oxidative metabolism via the tricarboxylic acid cycle. In the absence of
oxygen, pyruvate is converted to lactate by the lactate dehydrogenase reaction for anaerobic
glycolysis. An increase in the lactate-to-pyruvate ratio is shown to be a very sensitive
biomarker for impending cerebral damage. Glutamate, which acts as the primary excitatory
neurotransmitter in the brain, is released in excessive amounts following trauma, various
brain pathologies and ischaemic events, such as stroke, leading to excitotoxic injury and
neural cell death. Glycerol is known to be a sensitive marker for phospholipid cellular
membrane degradation after ischaemic cell injury as well. Detection of biomarkers using the
near real-time microdialysis method is a promising way of developing a better cerebral
monitoring system during aortic surgery to prevent neurological complications.
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