Christian Werner,
M.D.
(Professor of Anesthesiology)
Klinik für Anaesthesiologie
Technische Universität München, Klinikum rechts der Isar
Ismaninger Straße 22, 81675 Munich, Germany
Telephone: (89) 4140-4291; Fax: (89)
4140-4886
e-mail:
C.P.Werner@lrz.tu-muenchen.de
Cerebral ischemia and/or hypoxia may occur as a consequence of
shock, vascular stenosis or occlusion, vasospasm, neurotrauma, and
cardiac arrest. The ischemic/hypoxic insult evokes a cascade of pathophysiological
processes which will result in neuronal death. The first level of the ischemic
cascade is the accumulation of lactic acid due to anaerobic glycolysis.
This leads to increased membrane permeability and consecutive edema
formation. Since the anaerobic metabolism is inadequate to maintain
cellular energy states, the ATP-stores deplete and failure of energy-dependent
membrane ion pumps occurs. At the second stage of the ischemic cascade
terminal membrane depolarization along with excessive release of excitatory
neurotransmitters (i.e. glutamate, aspartate), activation of NMDA-
(N-methyl-D-aspartate), AMPA- (a-amino-3-hydroxy-5-methyl-4-isoxazolpropionat),
and voltage dependent Ca++
and Na+- channels. The consecutive Ca++ and Na+- influx leads to catabolic intracellular
processes. Ca++ activates
lipidperoxidases, proteases, and phospholipases which in turn increase
the intracellular concentration of free fatty acids (FFA) and free radicals.
Additionally, activation of caspases (ICE-like proteins), translocases,
and endonucleases initiate progressive structural changes of biological
membranes and the nucleosomal DNA (DNA fragmentation, inhibition of
DNA repair). Together, these events lead to membrane degeneration of
vascular and cellular structures and consecutive necrotic or programmed
cell death (apoptosis).
The strategies to
protect the brain from ischemic/hypoxic insults are based on the understanding
of these pathophysiological processes. Maintenance of normal to high cerebral perfusion
pressure, normoxia,
and surgical decompression
are by far the most important and effective neuroprotective interventions.
Besides these treatment modalities,
concepts of physical and pharmacological brain protection include interventions
to increase cerebral blood flow (CBF) in the ischemic territory, reduction
of cerebral metabolism and intracranial pressure (ICP), inhibition
of lactic acid accumulation and excitatory neurotransmitter activity,
prevention of Ca++ -
influx, inhibition of lipidperoxidation, and free radical scavenging.
The proposed mechanisms of anesthetic protection include reduction
of cerebral metabolism, and ICP, suppression of seizures and sympathetic
discharge, and a reset of thermoregulatory threshold. Additionally,
anesthetics may reduce intracellular Ca++- and free radical accumulation. However, the
clinical and experimental data remain controversial.
Studies in laboratory animals have shown that barbiturates as
well as propofol reduce infarct size and improve neurologic outcome
following focal or incomplete global cerebral ischemia as long as
physiological variables were controlled during the experiments.
While experimental data support the preventive neuroprotective effects
of hypnotic agents, the clinical evidence is less convincing. In patients
undergoing cardiac surgery with normothermic cardiopulmonary bypass
the infusion of thiopental (total dose during ECC: 39,5±8,4 mg/kg iv)
was able to reduce postoperative neuropsychological deficits. In
contrast, barbiturates infused to comatose patients within the first
hour following cardiopulmonary resuscitation were ineffective to
reduce mortality as well as neurological deficits in survivors compared
to standard ICU treatment. These data are consistent with the view that
the infusion of hypnotics prior
to focal but not global ischemic insults may increase the ischemic tolerance
of neurons. Barbiturates may be also beneficial in patients with severe
head injury and refractory intracranial hypertension. This conclusion
is related to a series of clinical studies where infusion of barbiturates
was effective in reducing intracranial pressure and likely the mortality
rate following brain trauma as long as systemic hemodynamic stability
was maintained. More recently propofol was suggested as an alternative
to barbiturates in patients undergoing cardiac surgery or for sedation
following head injury due to a favourable context-sensitive
half-time. While propofol did not reduce neuropsychological deficits
following cardiac valve surgery compared to sufentanil anesthetized
patients it turned out to be more effective in treating elevated ICP
with a similar neurologic outcome following head injury when compared
to an opioid-based sedative regimen.
NMDA-receptor antagonists
Glutamate and aspartate are known as excitatory neurotransmitters
which stimulate N-methyl-D-aspartate receptors (NMDA, Ca++ -
and Na+- influx). Since the activation of these receptors
initiates catabolic intracellular processes, blockade of NMDA-receptors
may protect cerebral tissue.
Ketamine, MK-801 (dizocilpine), aptiganel, dextromethorphan,
dextrorphan, and Mg++
represent non-competitive NMDA-
receptor antagonists. In animal models of focal (but not global) cerebral
ischemia and head injury ketamine as well as MK-801 reduced neuronal
injury and improved outcome. Likewise, infusion of the competetive NMDA-receptor antagonist
CGS 19755 (selfotel) reduced infarct size following focal and global ischemia.
Clinical trials using MK-801 were terminated due to toxic side effects
and the induction of mitochondrial vacuolization. The clinical development
of the antitussive agents dextromethorphan and dextrorphan was also terminated
because of side effects such as hallucination, agitation, and sedation.
Clinical trials in patients with acute stroke or head injury were either
prematurely terminated because adverse effects or did not show
improved outcome with the administration of the competetive NMDA-receptor antagonist selfotel or aptiganel.
The antiepileptic drug remacemide is the only NMDA receptor antagonist
with proven neuroprotective efficacy. In patients undergoing coronary
artery bypass surgery the perioperative administration of remacemide
significantly reduced postoperative neuropsychological deficits
along with some dizziness as the only relevant side effect.
Benzodiazepines
Midazolam and diazepam reduce neurologic deficit and increase survival
rate following incomplete global ischemia and hypoxia. Likewise, intraoperative
administration of diazepam reduced the incidence and extent of postoperative
neuropsychological deficits in patients undergoing cardiopulmonary bypass.
Despite the modest neuroprotective potential of benzodiazepines, midazolam and
diazepam are no first choice agents in patients with cerebral ischemia due to
their extended duration of recovery along with a delayed neurological
examination.
Alpha-2-adrenergic agonists
Clonidine and dexmedetomidine reduce peripheral but not central
sympathetic tone with consectivie modulation of circulating and synaptic
catecholamine concentration. Studies in laboratory animals
revealed a 37% decrease with theses combounds without changes in cerebral
metabolism. The cerebrovascular constriction is not associated with a reduction
in cerebral blood volume or intracranial pressure. Despite uncoupling between
cerebral blood flow and metabolism there is no evidence that infarct size
increases during cerebral ischemia. In
fact, clonidine and dexmedetomidine produced a dose-dependent decrease in
infarcz size and neurologic deficits in rats subjected to incomplete cerebral
ischemia and reperfusion.
In summary, intravenous anesthetic agents exert profound neuroprotection
in laboratory animals. In contrast, there is little
evidence for these neuroprotective effects in humans.