LOCAL ANAESTHETICS: REAPPRAISAL OF THEIR ROLE IN REGIONAL ANAESTHESIA AND PAIN MANAGEMENT NEUROPROTECTION

LOCAL ANAESTHETICS:

REAPPRAISAL OF THEIR ROLE IN REGIONAL ANAESTHESIA AND PAIN MANAGEMENT

NEUROPROTECTION

Eleni Moka

Anaesthesiology Department, Creta InterClinic Hospital, Heraklion, Greece

 

Introduction

Even nowadays, the treatment of ischaemic brain disease still remains a challenge for all clinical anaesthesiologists. Yet, there is no clinical evidence that any commonly used agent in the perioperative period affords significant neuroprotection against ischaemic injury. However, a large volume of experimental data confirms that among all anaesthetic agents, Local Anaesthetics (LAs) do hold at least some short term neuroprotective properties, in vitro as well as in vivo, in both animals and humans.

Traditionally, Local Anaesthetics (LAs) are used clinically for anaesthesia and analgesia purposes, either following surgery, or during the management of other acute and chronic pain conditions. The use of LAs has long been focused not only on the treatment of pain, but also of cardiac arrhythmias. According to classical knowledge, in both these settings, their efficacy – action is mainly based on Sodium (Na+) Channels’ Blockade. However, during the last decades, results of multiple publications suggest that LAs are able to interfere with other receptors. LAs not only block Na+ Channels, but also Calcium (Ca2+) and Potassium (K+) Channels, Transient Receptor Potential Vanniloid – 1 and NMDA receptors, as well as other ligand – gated receptors. In addition, they also disrupt the coupling between certain G proteins and their associated receptors.

Through such interference, LAs exert potent antinociceptive, antihyperalgesic, anti-inflammatory, antithrombotic, antibacterial and potential neuroprotective actions, leading to their administration in different settings, including postoperative ileus, neuroprotection, decompression sickness, cerebral air embolism, cancer recurrence and various types of inflammation.

Aim of the Lecture – Presentation

The aim of this lecture is to provide an overview of recent progress regarding LAs neuroprotective properties, in terms of new indications and limitations of their application. The lecture will commence with a brief summary of the main changes in brain metabolism, triggered by ischaemic / anoxic injury and neuronal death and will then continue with a review of the most important experimental and clinical data, showing that LAs exhibit neuroprotective properties both in vitro and in vivo. Finally, the clinical relevance of these findings and their prospects for the future will be discussed.

Hypoxia, Anoxia, Ischaemia and Neuronal Death: Pathophysiology

Considerable progress has currently been made in the understanding of the consequences of brain anoxia / ischaemia on nerve tissue metabolism and consequent neuronal viability. Impairment of blood and / or oxygen supply to the brain reduces ATP production and affects energy – dependent processes, such as function of the Na+ / K+ / ATPase transporter. Activation of ATP – dependent K+ channels, as well as of Ca2+ – activated K+ channels is interrupted, leading to initial neuronal hyperpolarization and electrical silence, immediately after ischaemia onset. Neuronal K+ transport loss results in its extracellular accumulation and in a subsequent slow neuronal cell depolarization. Once a threshold is reached, depolarization leads to the complete loss of membrane potential, with massive intracellular Na+ and Ca2+ entry. The release of excitotoxic amounts of glutamate from nerve terminals is triggered, activating both NMDA and AMPA receptors. This enhances Na+ and Ca2+ entry, in addition to K+ extrusion from the neurons through the glutamate receptor – coupled cationic channels.

During ischaemia, cytosolic Ca2+ concentration increases markedly, because of both NMDA receptors and voltage – gated Ca2+ Channels activation, but also due to the blockade of the Na+ / Ca2+ transporter and the release of Ca2+ from intracellular stores. The increase in cytosolic Ca2+ plays a prominent role in the development of ischaemic injury and of neuronal death by necrosis and / or apoptosis, through production of free radicals, DNA damage and proteolysis. Necrosis consists of cell disintegration, with a spreading tendency towards adjacent neurons, with simultaneous activation of glial cells and of immune system (acute inflammatory response). Apoptosis is a physiological process for eliminating unnecessary neurons, mostly during embryonic development, although during cerebral ischaemia, apoptosis is triggered as an actively programmed cell death. In contrast to necrosis, it does not damage adjacent neurons. Its initiation is attributed to cytochrome C release from mitochondria, producing ATP when oxygen is available and leading to activation of caspases and programmed cell death. Apoptosis is absolutely controlled and tightly regulated by both anti – apoptotic factors (bcl – 2) and pro – apoptotic ones (bax, bad), with tyrosine phosphorylation, triggered by growth factors (NGF, BDNF), also playing a major role in neuronal apoptosis inhibition.

Neuroprotection – Terminology

The term neuroprotection refers to the application of prophylactic interventions, prior or simultaneously with the hypoxic / ischaemic insult, aiming in enhancing neuronal «strength» and in improving neuronal cells survival rates (pretreatment). The term has been «extended» in order to include all interventions taking place after brain ischaemic / anoxic injury, targeting in the prevention of later – ultimate cellular damage (resuscitation). Every phase – step in the ischaemic cascade represents a potential target for pharmacological intervention. Currently, no pharmacological agent is considered a definite protective measure, in a way that it recommended as an absolute indication for neuroprotection. However, many drugs do deserve careful and specific – detailed attendance, with LAs being one of the most important categories.

Neuroprotective Effects of Local Anaesthetics (LAs)

The first step in the ischaemic cascade is Na+ influx. As a result, prevention or reduction of such a consequence offers to clinicians a potential mechanism for neuroprotection. The ability of LAs to block the hypoxia – induced alterations in Na+ influx, rather than blocking propagation of action potential, predicts their neuroprotective effects. This exciting area for systemic local anesthetic use – potential neuronal cells protection is significantly related to the seriousness of neurologic sequelae and relative paucity of therapeutic interventions, thus creating an important field of research, especially when taking into account the risk of many patients who undergo both cardiac and neurological surgery each year.

The neuroprotective effect of lidocaine (the LA that has been mostly studied) is reinforced by in vitro and in vivo, experimental and clinical studies in both animals and humans. Lidocaine blocks the voltage – gated Na+ channels, decreases energy demands, maintains ions homeostasis and finally protects the brain against ischaemic damage. Lidocaine is considered a very promising agent in the field of neuroprotection because a) it is a local anaesthetic (familiar to all clinicians and easy in pharmacological «manipulation»), b) it acts in the early stages of the ischaemic «cascade», thus interrupting the following sequelae of all pathophysiological interactions, especially when administered prophylactically and, finally c) its actions have been described at doses that have been applied in various clinical situations.

In vitro studies results conclude that lidocaine limits ischaemic injury in rat hippocampal slices, subjected to 10 min anoxia and that low concentrations of lidocaine and tetrodotoxin improve recovery of CA1 pyramidal cells, through reduction of Na+ influx and initiation of depolarization. Higher concentrations can partially restore ATP production and may also block the increase of intracellular Na+ accumulation and depolarization induced by hypoxia, but do not block neuronal activity during normoxic conditions. In addition, a clinical antiarrhythmic dose of lidocaine (4 mgr / kg) increased the number of surviving CA1 pyramidal neurons and preserved cognitive function, following transient global ischaemia in rats, indicating that lidocaine is a good candidate for clinical brain protection.

Several in vivo experimental studies on rats have shown the neuroprotective effects of lidocaine at antiarrhythmic doses. Lei et al reported that low – dose lidocaine, infused 30 min before focal cerebral ischaemia led to a significantly reduced infarct size, improved neurologic outcome and resulted in less post – ischemic weight loss. A more recent study by the same group of investigators has also shown that a similar antiarrhythmic dose of lidocaine, also given 30 min before onset of ischaemia, attenuated neuronal apoptotic cell death in the penumbra and showed a similar reduction in infarct size. Even though these studies involved pre – ischaemic administration of lidocaine, Lei et al have also shown that lidocaine has neuroprotective effects when administered 45 min after the ischaemic event, by improving evoked potentials values. Although the size of the infarct was not significantly reduced in the lidocaine – treated rats in this study, they reported an increase in the number of surviving neurons in both the ischaemic penumbra and the ischaemic core, an improvement in the neurological outcome, and an increase in post – ischaemic body weight. Similarly, Cao et al reported that both pre – insult and post – insult administration of lidocaine attenuated cell death, either before or after 10 min of oxygen glucose deprivation in the rat hippocampus.

Additionally, lidocaine significantly inhibits the Acid Sensing Ion Channel Currents (ASIC currents) in mouse cortical neurons by up to 90% approximately. The inhibition is reversible and dose – dependent. The effect is rapid and does not depend on pH. In Chinese hamster ovary cells, expressing different ASIC subunits, lidocaine inhibits the ASIC1a current without affecting the ASIC2a current.

Furthermore, based on the assumption that excitotoxic neuronal injury from ischemia may be reduced by local anesthetics and according to the results of an experimental study examining the neuroprotective effects of intrathecally administered bupivacaine and hypothermia in a rat model of transient spinal cord ischemia, it is collectively suggested that intrathecal bupivacaine does not provide neuroprotection during normothermic transient spinal cord ischemia in rats, although it enhances the neuroprotective effects of hypothermia. In this study, after reperfusion, the motor and sensory deficit scores of the normothermia (NT) group were significantly higher than those of the hypothermia (HT) and bupivacaine – hypothermia (BHT) ones. Significant differences were evident in the motor and sensory deficit scores between the HT and BHT groups at 24 h. Neuronal cell death and immunoreactivity of HSP70 were frequently observed in the NT and BT groups, but not in the HT and BHT groups.

Based on the above, one may understand that an antiarrhythmic dose of lidocaine, given before, during or after transient focal cerebral ischemia, significantly reduces infarct size and improves neurological outcome. Blocking apoptotic cell death in the penumbra involving cytochrome C release and caspase 3 activation may also play a role in these effects.

At a clinical level, several studies have previously shown that antiarrhythmic or even lower doses of lidocaine demonstrate neuroprotective effects in humans. These potential properties are of great importance, since the severity of perioperative neurologic sequelae and the relatively limited therapeutic interventions that are available make this an important area of research. Postoperative neurocognitive decline is detected in more than 50% of patients post cardiac surgery, being still present 6 months later in 30%.

Interestingly, lidocaine possesses neuroprotective effects in cardiac surgical patients. Mitchell et al found a better outcome in patients undergoing mitral and aortic valve surgery, while Wang et al observed improved early cognitive recovery in CABG patients. Cognitive decline is associated with the occurrence of silent brain infarcts. There is thus both experimental and clinical evidence to suggest that lidocaine may be neuroprotective in cardiac surgical patients. In a prospective, randomized double – blind, placebo – controlled study, Mathew et al investigated whether a continuous intravenous infusion of lidocaine (bolus 1mg/kg, followed by 1mg/min for the next 48h) would reduce postoperative cognitive dysfunction after cardiac surgery, using cardiopulmonary bypass (CPB). The authors concluded that lidocaine did not reduce the incidence of cognitive dysfunction, but in non – diabetic patients a secondary analysis did show a neuroprotective effect, which was still present 1 year after surgery. This study suggests that not all, but certain patients may benefit from such treatment.

Additionally, since neuroprotection in the setting of severe head injury (SHI) remains an unsettled problem some scientists have tested a combination of high – dose magnesium and low – dose lidocaine, infused over 3 days, in 32 consecutive patients admitted to the emergency department of a large tertiary referral centre, during a pilot study to assess safety. This combination appeared indicated to protect both gray and white matter from secondary injury following SHI. No toxicity was observed, mortality was lower than published statistics and these results seem to open the stage to a controlled randomized study.

In the majority of experimental and clinical studies, lidocaine was administered systematically. Now the question that arises is if LAs administered through other routes still exert protective effects on neuronal cells. There is accumulating evidence that intrathecal LAs (for spinal anaesthesia) may themselves be neurotoxic – although occasionally protective, and that lidocaine is more neurotoxic compared to others, with ropivacaine being the least toxic one and levobupivacaine presenting a more favourable profile over the racemate.

In an in vitro experiment, primary cultures of mouse cortical cells, containing both neurons and astrocytes, were exposed to 100 microM NMDA for 10 min for the induction of excitotoxic neuronal death. This treatment killed 70 – 80% of the neuronal population, as assessed 24 h after the excitotoxic pulse. In this particular model, both levobupivacaine and bupivacaine were neuroprotective against NMDA toxicity. However, neuroprotection by levobupivacaine was seen at lower concentrations (with respect to bupivacaine) and was maintained at concentrations of 3 mM, which are much higher than the plasma security threshold for the drug in vivo. In contrast, no protection against NMDA toxicity was detected when 3 mM concentrations of bupivacaine were applied to the cultures. These data show a better neurotoxic profile of levobupivacaine as compared to racemic bupivacaine, and are indicative of a safer profile of levobupivacaine in clinical practice.

Neither the clinical implications nor the cellular mechanisms of LA neurotoxicity have been fully elucidated, but accumulating evidence strongly suggests that lidocaine has a narrow therapeutic index with clinical implications for both spinal anaesthesia and attempts to use LAs as neuroprotective agents, by decreasing neuronal metabolism. The direct neurotoxicity of LAs that will be discussed here is distinct from the global CNS toxicity seen with inadvertent intravascular overdose, and from other causes of neurologic injury after spinal anesthesia, such as mechanical needle trauma and epidural hematoma.

LAs induce multiple derangements in neuronal homeostasis, depending on the dose and exposure time. Toxicity is not mediated by the desired pharmacological effect of LAs, Na+ blockade, since an equipotent dose of tetrodotoxin, a structurally unrelated Na+ blocker, is not neurotoxic. Generally, lidocaine is more toxic than equipotent bupivacaine; other comparisons are either incomplete or indefinite. It is not known if there is a single proximal insult leading to all others, or whether there are multiple insults leading to multiple mechanisms of neuronal death or injury, in case LAs neurotoxicity is a consolidated fact. It is tempting to hypothesize that higher doses cause neuronal death or long – lasting injury by a mechanism distinct from transient injury associated with TNS at lower doses, but this is not established. LAs increase cytoplasmic calcium. The biphasic calcium response involves release from internal stores, including the endoplasmic reticulum, as well as influx of calcium across the plasma membrane for higher concentrations. LAs also cause a rapid decrease in mitochondrial membrane potential which is initially reversible and not due solely to uncoupling. A direct effect of LAs on membrane permeability has been shown. Very low concentrations of lidocaine reversibly inhibit axonal transport. Tetracaine induced multiple members of the mitogen – activated protein kinase family in PC12 neurons, but some kinases were harmful and some were protective.

As it has already been mentioned, lidocaine is cerebroprotective in human as well as animal studies, at plasma concentrations well below the ED50 for Na+ channel block that are not toxic in the models reviewed above. The mechanism is not clear. The ability of such low concentrations of lidocaine to provide spinal neuroprotection has not been tested. Three of four animal studies using much higher CSF concentrations of LA to providedense spinal anesthesia have reported spinal cord neuroprotection in various ischemic models. In the nonprotective study, the tip of the spinal catheter was placed at the cauda equina and there was evidence of injury (elevated glutamate) in some animals. In the protective studies, the catheter was placed at L2-5 or higher, which probably provided better mixing of LA with CSF. Further study is required before spinal anesthesia can be recommended as neuroprotection. The neurotoxicity of LAs suggests particular caution when considering spinal LA as prophylactic neuroprotection in a situation where bad outcomes are not frequent.

As experience with dose – response and mechanism of the action of a particular compound expands, it is evident that multiple mechanisms may exist for any given agent when the full dose – response curve is explored. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposure, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose – dependent transitions in the principal mechanism of toxicity may occur and could have significant impact on the interpretation of data sets for risk assessment. The principle explored is that each saturable or inducible process that occurs as part of the overall chemical disposition and / or biological response represents a potential point of departure from linearity in the dose – response relationship. Saturable and / or inducible processes that contribute to the pharmacokinetic characteristics include absorption, distribution (protein binding, active transporters), elimination, and chemical transformation (activation and detoxification). Pharmacodynamic examples include receptor interactions (affinity constants, finite receptor numbers, and multiple receptor types), repair / reversal (DNA repair, receptor reactivation, protein synthesis, and cell replacement), and altered homeostasis (induction, metabolic switch, cell proliferation, and apoptosis). Using the effects of increasing doses of cocaine on PC12 cells in culture, recent data demonstrate that the mechanism of cell death switches from apoptosis to necrosis as the dose is increased. This example serves to document that dose – dependent transitions in mechanism can occur and to provide an opportunity for discussing the potential impact of this phenomenon on the risk assessment process.

Conclusions

To date, large trials attempting to demonstrate pharmacological neuroprotection with perioperative LAs administration have produced disappointingly small reductions in morbidity and mortality and experimental data produce ambiguous results and inconsistent conclusions. The reasons for this may include lack of convincing experimental data, underpowered clinical trials, heterogeneity of patients, timing of drug administration, and the difficulty in getting the local anaesthetic agent to the ischaemic zone.

However, systemic administration of LAs may protect against brain ischaemia in some clinical situations. During cardiac surgery, lidocaine may protect against the neurocognitive sequelae of micro embolization, especially in high – risk perioperative situations. In addition, LAs may interfere with neuroprotective measures of spinal cord ischaemia during major cardiovascular or orthopaedic procedures. Their neuroprotective effects when administered via alternative routed still remains unexplored and necessitates illucidation. It is fascinating that more than decades after the introduction of LAs for perioperative analgesia, we may still discover new properties and anticipate new applications of this class of drugs. Various types of inflammation including neuroprotection, may be positively influenced by the application of LAs. These issues are without doubt the challenges of the coming years.

 

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