The primary objective of this study was to evaluate the impact of neuroprotection, administered during carotid endarterectomy, on brain metabolism. The secondary objective was to assess the impact of resulting changes in brain metabolism on the clinical outcome.
A total of 35 patients underwent carotid endarterectomy with prophylactic combined neuroprotection (Sendai cocktail: Manitol, Phenhydan, Solumedrol, Tokoferol; Cerebrolysin; fraction of inspired oxygen (FiO2) =1, middle arterial pressure (MAP) = 100 mmHg, total intravenous anesthesia - TIVA). The influence of neuroprotection on brain metabolism (S100B, glycaemia, lactate, pH, jugular vein bulb oxygen saturation - SvjO2) was evaluated. Metabolic parameters were acquired from the jugular bulb during surgery, just before unclamping of the vessel. The clinical outcome was evaluated by NIHSS (National Institutes of Health Stroke Scale). There were 35 patients in the control group who where operated on without any neuroprotection. The results from both groups of patients were compared and statistically analyzed.
Postoperative NIHSS did not change in any patient in either group. An intraoperative shunt was not inserted in any patient in either group. In the group with neuroprotection there were significantly higher levels of S100B (median 0.117 vs. 0.088; p<0.0182), lactate (median 1.92 vs. 1.020; p<0.0006), glycaemia (median 9.5 vs. 8.2; p<0.0243), and SvjO2 (median 0.79 vs. 0.65; p<0.0001). There were no postoperative changes to NIHSS in either group.
Neuroprotection administered before carotid endarterectomy influences some parameters of brain metabolism both positively and negatively, but with no impact on clinical outcome.
neuroprotection, carotid endarterectomy, brain metabolism, cognitive functioning
endarterectomy (CEA) is an effective operation in the primary and
secondary prevention of stroke on the condition that morbidity and
mortality (MM) do not exceed the recommended grade (1). The
complications of CEA can be divided into 3 groups: neurological,
internal and surgical. Intraoperative strokes, caused by embolisation
or hypoperfusion, are largely accountable for neurological MM.
Neurosurgeons try to minimize the risk of intraoperative stroke or
neurological deficit in the event of a stroke. The occurrence of a
stroke during an operation designed to prevent strokes is always a
very frustrating complication.
possibility of reducing the consequences arising from intraoperative
stroke is to use neuroprotection. Neuroprotection is a strategy that
antagonizes the sequence of injurious biochemical and molecular
events that, if left unchecked, would result in ischemic injury (2).
In spite of the demonstrable effects of many agents in animal models,
until now, none of the tested neuroprotective agents have been shown
to improve the outcome in a phase III clinical trial (3). The main
cause of the failure of neuroprotection in stroke patients is an
over-extended therapeutic window (3, 4). In preclinical research,
neuroprotection becomes effective within a six hour therapeutic
window. The most significant effect was achieved when administration
was performed before the occurence of a stroke (5). This finding has
led to a new concept of prophylactic neuroprotection (6).
Prophylactic administration of neuroprotection prior to risk
procedures (CEA is the typical example), could be beneficial for
However, the incidence of intraoperative ischemic injury during CEA
is very low. In big studies its frequency runs to anything from less
than one to a few percent. It would be necessary to evaluate groups
of thousands of patients if we wish to assess the impact of
neuroprotection on the incidence of strokes. Such a high number is
achievable only in prospective, international, multicentric studies.
No such study has yet been published. From the definition of
neuroprotection it is evident that biochemical changes precede a
stroke. Therefore we evaluated the impact of neuroprotection on
brain metabolism and its association with resulting clinical
underwent elective CEA due to symptomatic carotid stenosis were
submitted to this
prospective study. The criteria for acceptance to the study were a
post TIA condition or minor ischemic stroke with a minimal residual
neurological deficit (Institutes of Health Stroke Scale - NIHSS <
3), CT without new ischemia and symptomatic carotid stenosis of more
whose actual clinical status, insufficient collateral supply or
condition of cerebral tissue could influence the evaluated parameters
(operation within 14 days of the origin of the stroke, neurological
instability, significant residual neurological deficit, contralateral
carotid obliteration, new hypodensity on CT), were not submitted to
A total of 35 patients underwent carotid endarterectomy with combined
prophylactic neuroprotection (Table 1). The neuroprotective
strategy involved a Sendai cocktail (20% Manitol 150 ml, Phenhydan
500mg, Solumedrol 1g, Tokoferol 300 mg) and 50 ml Cerebrolysin
administered at the beginning of anesthesia, fraction of inspired
oxygen (FiO2) =1 and middle arterial pressure (MAP) = 100
mmHg at the time of vessel clamping. Total intravenous anesthesia
(Propofol) is a standard part of neuroprotection.
technique and intraoperative electrophysiological monitoring (EEG,
SEP n. medianus) were used during operations.
There were 35
patients in the control group who where operated on without any
neuroprotection under local anesthesia.
objective of this study was to evaluate the impact of combined
neuroprotection, administered during carotid endarterectomy, on brain
metabolism (S100B, glycaemia, lactate, pH, jugular vein bulb oxygen
saturation - SvjO2). Metabolic parameters of the brain
were ascertained during surgery from the homolateral internal jugular
vein just before unclamping of the vessels. The secondary objective
was to assess the impact of resulting changes in brain metabolism on
clinical outcome, which was scored using NIHSS.
from both groups of patients were compared and statistically
analyzed. Statistica 9.0 Software was used.
neuroprotection was performed over a two year period on 35 patients
(25 men, 10 women) aged 44 -77 (median 65). Nine patients had a mild
neurological deficit (NIHSS 1-3) before surgery while the others had
normal neurological status. CEA without neuroprotection was performed
on a control group during the same two year period. Ten patients had
a mild neurological deficit (NIHSS 1-3) before surgery, the others
had a normal neurological status.
significant differences in metabolic parameters were demonstrated in
S100B protein, lactate, glycaemia and SvjO2.
neuroprotection group, compared with the control group, there were
significantly higher levels of S100B (min 0,018, median 0,117, max
0,335 vs. min 0,022, median 0,088, max 0,262; p<0,0182), lactate
(min 0,050, median 1,92, max 3,540 vs. min 0,670, median 1,020, max
3,580; p<0,0006), glycaemia (min 5,1, median 9,5, max 17,6 vs. min
4,8, median 8,2, max 16,0; p<0,0243), and SvjO2 (min
0,56, median 0,79, max 0,97 vs. min 0,51, median 0,65, max 0,83;
p<0,0001) (Graph 1 – 4).
intraoperative stroke was detected in either group, preoperative and
postoperative NIHSS did not change in any patients. We did not detect
any statistically significant difference between the follow-up and
control groups in either preoperative or postoperative neurological
status (NIHSS 0 – 74% vs. 71%, NIHSS 1 – 17% vs. 17% - , NIHSS 2
– 3% vs. 9%, NIHSS 3 – 6% vs. 3%). Recognized differences in
brain metabolic parameters did not influence clinical outcome.
We had two
reasons to do the presented research. The first was a very low
incidence of symptomatic intraoperative ischemic stroke (0,5 %) and
the low frequency of shunt insertion (2,75 %) in our cohort of CEA.
We used shunt significantly less than in published literature (6-16%)
(7-9). We interpret our positive results as a positive influence of
the mentioned combination of neuroprotective strategies and general
anesthesia that we have used over a long period in standard practice
motivation to research was the idea of new concept of prophylactic
neuroprotection, which is more beneficial, if it is administered
before stroke (6). The combination of TIVA and prophylactic
neuroprotective strategies is a typical example of mentioned concept.
The effect of
our neuroprotective strategies was only recorded, as in all
neuroprotective agents used until now, in experimental trials and in
clinical trials of phase I and II (11-15). The combination of
neuroprotective agents (cocktail), which work on more levels of
ischemic cascade, is more effective (4). The most significant
neuroprotective effect was demonstrated when administration was
performed before stroke (5). Our method, which combines a number of
neuroprotective strategies (pharmacological, physical) administered
preventively before the occurrence of stroke, fulfills both
requirements. General anesthesia is an irreplaceable part of the
neuroprotective agents used and, moreover, general anesthesia is the
condition for administration of a whole group of neuroprotective
agents (FiO2 = 1). There is much reliable evidence of the
prophylactic effect of neuroanesthesia (16).
Patients of the
neuroprotection and the control group did not significantly differ in
regard to demographic characteristic, initila clinical status or
timing of operation. All patients were monitored continuously for 24
hours in a neurosurgical intensive care unit, where NIHSS was also
assessed first. We were able to detect reliably stroke as well as
minor TIA and other manifestations related to intraoperative
hypoperfusion or microembolisation (confusion, delirium, cognitive
deterioration). In spite of the accuracy of clinical observation none
of the aforementioned incidents were noted. NIHSS neither changed nor
differed in either group.
exception of patients after a major stroke, we operated on all
patients with symptomatic carotid stenosis as soon as possible
according to recent guidelines (1). In no case was the timing of
operations delayed to allow for the acceptance criteria of the study.
The long time period from the stroke to surgery is due to the late
transmission of patients from neurological departments and,
paradoxically, due to no submission of patients operated on within
the required 14 days of the stroke.
of brain metabolism were determined from jugular bulb blood acquired
by puncture of the internal jugular vein during the operation and
just before unclamping of the vessel. During this period the
homolateral brain hemisphere is supplied by a more or less sufficient
collateral blood supply and hence there is the most probable
potential for hypoperfusion with a negative impact to brain
of 100B protein were surprisingly found in the neuroprotection group
(Graph 1). S100B protein is a calcium linking protein which is used
as a prognostic marker of brain injury. Its biological half-life is
unknown (17). Lavicka et al mentioned that, in mild traumatic brain
injury, 100B protein returns to normal levels within three days (18).
Thus, to avoid having the 100B protein level influenced by their
primary stroke, our patients were operated on within 14 days and the
patients with major stroke were not submitted to the study. We did
not record any correlation between S100B protein and timing of the
surgery. The levels of S100B protein were significantly higher
(p<0,0182), but in most cases (83%) still within standard range
(0,001-0,14 microg/l). Extracerebral
resources of S100B protein could not be of use in our study.
neuroprotection group there were also surprisingly significantly
higher levels of lactate (p<0,0006) in
spite of the time period of FiO2 = 1 during surgery (Graph
2). The oxygen supply in arterial blood exceeded its consumption by
more than under physiological conditions (19). Lactate originates
from anaerobic glycolysis and its increase corresponds to the
restriction of oxidative phosphorylation. The rise in lactate could
be caused by hypoxia, arterial hypotension or significant
intraoperative blood loss (20). Nevertheless, at the beginning of
anesthesia, during anesthesia, and during surgery, none of the
mentioned incidents were registered. Lactate, along with the rest of
the parameters, was moreover tested at the end of the time period
when the patient was ventilated with 100% O2.
The elevation of lactate was not accompanied by lactate
significantly higher level of glucose was also found in the
neuroprotection group (p<0,0243) (Graph 3). It is important that
there was no difference between the two groups in either the
incidence of diabetes mellitus or in the correlation of higher
glycaemia and the incidence of DM. The metabolism of glucose, lactate
and oxygen are closely associated with each other. Hyperglycaemia
exceeds the size of ischemia and induces anaerobic glycolysis which
causes an elevation of lactate (12). Hyperglycaemia is an
unambiguously harmful factor during brain ischemia (21). Elevated
glucose accompanies stroke in 50% (stress hyperglycaemia) (13). This
explanation can not be used in our study because none of the patients
suffered intraoperative stroke. On the other hand, a higher level of
glycaemia in blood from jugular vein can be connected with the lower
rate of glucose (CMRGl) during lower energy consumption of the brain,
which is influenced by neuroprotection. This interpretation is
supported by significantly higher SvjO2
in the neuroprotection group, which can be explained by
lower oxygen consumption (reduced cerebral metabolic rate of oxygen -
CMRO2) or its elevated supply (Graph 4). Administered
neuroprotection is probably involved in both mentioned mechanisms.
The average oxygen consumption (O2ER - oxygen extraction
ratio) was lower in the neuroprotection group in comparison with the
control group (21% vs. 33%).
levels of metabolic markers can be interpreted as controversial
(Table 2). Some markers were influenced positively by
neuroprotection, others negatively. Surprisingly, higher S100B
protein and lactate in the neuroprotection group indicate a negative
impact of neuroprotection. There was also an elevated level of
glucose in the neuroprotection group. In spite of the acceleration of
pathophysiological changes and the enlargement of stroke volume by
hyperglycaemia in the experiment, it can be considered as a
manifestation of lower metabolic consumption of the brain. From this
point of view hyperglycaemia can be interpreted as a positive
consequence of neuroprotection. Higher SvjO2 in the
investigated group is an indisputably positive effect of
We tried to
detect a correlation between the metabolic markers in our study.
However, a statistically significant correlation between the elevated
levels of S100B protein, glucose and lactate was not proved.
The effect of
combined neuroprotective strategies administered before CEA is
controversial. Neuroprotection used in our study influenced some
brain metabolic parameters, both positively and negatively, however
without impact on the clinical outcome. We did not prove a
statistically significant correlation between monitored metabolic
Our unexpected disappointment with the inconclusive results
corresponds with the general disillusion from the failure of
neuroprotection in clinical trials. According to the latest
guidelines of the European Stroke Organisation (ESO) there is no
recommendation for the administration of neuroprotection in patients
with acute stroke (class I, level A). It is not expected that the
administration of neuroprotection will become part of “evidence
based medicine” in the near future. The use of neuroprotection in
patients with acute stroke is based on experimental trials. It is
necessary to take into account the cost benefit ratio when
neuroprotection is used.
In spite of the failure of neuroprotection in the treatment of acute
stroke, it is necessary to continue doing clinical research and
importantly not to avoid publishing negative results.
- FiO2 -
fraction of inspired oxygen
- MAP – middle
- TIVA – total
– jugular vein bulb oxygen
- NIHSS -
National Institutes of Health Stroke Scale
- CEA – carotid
- MM - morbidity and
- TIA – transient
- CT – computed
- EEG -
- SEP –
somatosensory evoked potentials
- DM – diabetes
CMRGl – cerebral metabolic rate of glucose
CMRO2 – cerebral metabolic rate of O2
O2ER - oxygen extraction ratio
- ESO - European
Corresponding author contact:
Jan Mracek, MD
Department of Neurosurgery, Charles University Hospital Pilsen
Alej Svobody 80, Pilsen, 304 60, Czech Republic
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