The use of muscle relaxants is a widely adopted practice in general anaesthesia and is commonly recommended in anaesthesia protocols designed for neurosurgery. However, at a time where guidelines and standard recommendations are regularly questioned, the rationale for using muscle relaxants in neurosurgical anaesthesia needs to be reassessed. Neurosurgery has changed considerably over recent years, moving from conventional craniotomies towards minimally invasive techniques and functional procedures . Neuroanaesthesia has also substantially evolved, taking benefit from new volatile agents, short-acting drugs and new administration techniques like target-controlled infusions. The time has come for neuroanaesthesiologists confronted by those important changes to question their ritual practice. Why use muscle relaxants in neurosurgical anaesthesia? Are there any reasons for not using them? Do those drugs have specific effects on the central nervous system? Should muscle relaxants be indicated, what will guide choice and good practice with respect to their specific side-effects and potential interactions in neurosurgical patients?
To use or not to use muscle relaxants
Basically, the three main reasons for using muscle relaxants during anaesthesia designed for general surgery involve provision of excellent intubating conditions, control of mechanical ventilation of the lungs and facilitation of the work of the surgeon. Endotracheal intubation can be easily performed without muscle relaxants, although sometimes at the expense of haemodynamic alterations . Artificial ventilation can be easily controlled during anaesthesia without muscle relaxants. Lastly, there is no muscle inside the skull that could be paralysed to improve the neurosurgeon's performance. On the other hand, numerous neurosurgical procedures do not absolutely require muscle relaxants or even contraindicate their use. Current neurosurgical techniques favour minimally invasive surgery, endoscopy, stereotactic approaches and functional procedures. Preserving or restoring brain function has become a primary objective in neurosurgical practice. For example, specific monitoring techniques such as motor-evoked potentials are advocated in surgery of tumours located in motor areas of the cortex or in the spinal cord. In spinal cord surgery, recording intraoperative motorevoked potentials after electrical spinal cord stimulation is feasible under conditions of controlled neuromuscular blockade . A constant degree of neuromuscular blockade has even been considered useful to eliminate patient motor activity that could interfere with surgery and to minimize amplitude fluctuations of the evoked responses . Regarding cortical motor-evoked potentials, partial neuromuscular blockade does not reduce latency but may reduce the amplitude of transcranial magnetic motor-evoked responses [4,5]. However, intraoperative monitoring of motor evoked responses to direct electrical stimulation of the cerebral cortex in the absence of neuromuscular blockade has been proved a feasible and reliable technique . The intraoperative facial nerve monitoring during cerebellopontine angle surgery is feasible under controlled neuromuscular blockade , but those conditions have been recently reported to affect adversely postoperative facial nerve function . In so far as some degree of neuromuscular blockade may confound the reliability of the electrophysiological response during surgery and hence the patient's outcome, its recommendation as a standard of the anaesthetic technique in some specific neurosurgical procedures appears questionable. Awake craniotomies for epilepsy surgery or surgery involving the eloquent cortex, and any surgical procedure performed in sedated patients obviously preclude the use of muscle relaxants. There is therefore growing evidence that some conventional and also more recent neurosurgical techniques do not require or even preclude the use of muscle relaxants in clinical anaesthesia.
Classical concepts revisited
For many years, muscle relaxants were considered an integral part of the neurosurgical anaesthesia regimen, mainly because they were thought to improve surgical conditions without being deleterious to the brain. The neurosurgical benefit expected from neuromuscular blockade is twofold: avoiding coughing, movements and their potentially disastrous consequences; and decreasing the intracranial pressure by lowering intrathoracic and central venous pressures. The absence of any deleterious effect is ascribed to the fact that muscle relaxants are generally believed not to cross the blood-brain barrier and hence to exert only indirect effects on the central nervous system.
The absence of coughing and movements does not necessarily guarantee stable intracranial pressure and brain relaxation. Indeed, the increase of intracranial pressure associated with endotracheal intubation may result from haemodynamic modifications induced by the stimulation of the nervous sympathetic system. Although neuromuscular blockade can suppress coughing, it does not ensure haemodynamic stability, which strongly depends on an appropriate level of analgesia and anaesthesia [2,9]. Movements that occur during surgery in response to noxious stimulation are involuntary withdrawal movements resulting from spinal cord reflexes. According to Lanier and colleagues, increases in intracranial pressure that accompany movements in intubated patients may arise from two complementary factors: a passive congestion of the cerebral vessels and active cerebral vasodilatation . The passive venous congestion reflects an increase in the central venous pressure that can be reduced by elevating the head. The active cerebrovascular dilation correlates with electromyographic activity and is mediated by ascending neural pathways, which transmit proprioceptive information . If the intracranial response is abolished by muscle relaxants, it is also exquisitely and primarily dependent on the level of analgesia and anaesthesia. On the other hand, although muscle relaxants decrease intracranial pressure by lowering intrathoracic and central venous pressures, brain relaxation may be achieved using different drugs and techniques in the absence of neuromuscular blockade.
Another common assumption that deserves re-evaluation is that non-depolarizing neuromuscular blocking drugs - because they are highly ionized - do not cross the blood-brain barrier and have only indirect effects on the central nervous system. In fact, tubocurarine has been found in the cerebrospinal fluid of patients after a single intravenous injection . Vecuronium, atracurium and laudanosine, the atracurium major metabolite, have also been measured in the cerebrospinal fluid in patients with sepsis or subarachnoid haemorrhage [12-15]. Therefore, several reports attest that muscle relaxants do cross the blood-brain barrier, at least under certain conditions, and can directly affect the central nervous system. Those agents have been reported to cause autonomic dysfunction, weakness, prolonged neuromuscular blockade, seizures and neuronal death [16-20]. It seems that muscle relaxants may have an excitatory effect on the central nervous system that would result from their interaction with brain nicotinic acetylcholine receptors . Pancuronium and vecuronium, but not atracurium and laudanosine, have been shown to provoke an intracellular calcium increase in cortical slices that is prevented by low concentrations of tubocurarine and by phenytoin . Chiodini and colleagues have reported that atracurium and laudanosine, as opposed to pancuronium and vecuronium, enhance excitatory transmission and block inhibitory γ-aminobutyric acidA-mediated synaptic responses in hippocampal slices . Recently, they have demonstrated that atracurium and laudanosine interact with different types of neuronal nicotinic acetylcholine receptors at clinically relevant concentrations .
Factors affecting the choice of a muscle relaxant
The choice of a muscle relaxant is usually governed by three types of factors: the absolute criteria of the ideal muscle relaxant, the reason why muscle relaxation is required, and some considerations related to patient and pathology. The absolute criteria of the ideal neuromuscular blocking drug mainly include a non-depolarizing mechanism of action, a rapid onset, a short or intermediate duration of action, no organ-dependent metabolism or no metabolism at all, no cumulative effect, no antagonism required or some facility to 'reverse', no side-effects, and low cost. According to what has been previously discussed, facilitating endotracheal intubation is probably one of the main reasons for using muscle relaxants in neurosurgical anaesthesia. In this situation, the degree of emergency, the risk for aspiration of the gastric content and the anticipation of difficult intubating conditions will guide the choice of the muscle relaxant. Finally, specific criteria related to neurosurgical anaesthesia refer to the absence of interaction with brain metabolism, cortical electrical activity, cerebral haemodynamics and intracranial pressure, as well as with patient pathology and therapeutics. Beside a potential excitatory effect, the two major concerns of muscle relaxants in neurosurgical anaesthesia include their effects on cerebral haemodynamics and intracranial pressure, and specific pharmacodynamic alterations related to patient pathology and anticonvulsant therapy.
An increased sensitivity to succinylcholine and some degree of resistance to non-depolarizing muscle relaxants are quite common in neurosurgical patients. Those modifications may reflect a pathology associated with an upregulation of acetylcholine receptors or may be seen in patients receiving chronic anticonvulsant therapy. Upregulation of acetylcholine receptors is encountered in denervation syndromes resulting from direct muscle injuries and from lower or upper motor neuron injuries, but may also be associated with immobilization and atrophy . On the other hand, most anticonvulsants have pre- and postjunctional effects similar to those of non-depolarizing muscle relaxants . By inhibiting the presynaptic release of acetylcholine, decreasing post-tetanic potentiation and reducing the end-plate potential, they simulate a state of chronic chemical denervation associated with a proliferation of acetylcholine receptors. The upregulation resulting from upper motor neuron lesions is extensive, while that in response to anticonvulsants is thought to be mild due to the weak effects of those drugs at the neuromuscular junction . In addition to the pharmacodynamic mechanism, the resistance to non-depolarizing muscle relaxants induced by chronic anticonvulsant therapy may also be explained by pharmacokinetic considerations that involve both an increased hepatic metabolism and clearance by induction of specific enzymes in the cytochrome P450 system, and an increased binding of muscle relaxants to plasma α1-acid glycoprotein [27-30]. Phenytoin and carbamazepine have been shown to decrease acetylcholine release at the neuromuscular junction and to produce a dose-related inhibition of the end-plate potential [31,32]. Those effects simulate a state of denervation associated with a mild upregulation of acetylcholine receptors and favour the pharmacodynamic hypothesis. In contrast, Platt and Thackray have shown that an exaggerated rise in serum potassium after succinylcholine does not occur in patients with demonstrated resistance to vecuronium from chronic phenytoin therapy, suggesting that upregulation of acetylcholine receptors is an unlikely mechanism . Another argument supporting the pharmacokinetic mechanism is that carbamazepine and phenytoin are potent inducers of liver-metabolizing enzymes and increase the plasma levels of acute phase reactant proteins which are binding sites for many drugs, including muscle relaxants [27-30,34]. Protein binding has been suggested to explain the resistance to atracurium in rats . Clearance of vecuronium has been shown to be twofold increased in epileptic patients receiving chronic carbamazepine therapy compared with the control group . However, a simple relationship between phenytoin concentration and induction of cytochrome P450 or α1-acid glycoprotein has not been found . According to Hans and colleagues, enzyme induction plays an important role in the accelerated recovery from paralysis to non-depolarizing muscle relaxants in patients receiving anticonvulsant therapy, but there is no correlation between the degree of resistance and the plasma level of anticonvulsant medications . At present, the resistance phenomenon to non-depolarizing muscle relaxants in patients under chronic anticonvulsant therapy is well established, but the relative contribution of the two hypothetical mechanisms involved in that process remains to be clarified.
Which muscle relaxant to choose in neurosurgical patients?
Succinylcholine is mainly used to facilitate endotracheal intubation. It is usually selected in emergency situations due to its characteristics and potential side-effects and is commonly believed to increase cerebral blood flow and intracranial pressure. The proposed mechanism for that increase is a cerebral-exciting effect caused by muscle spindle activity that results from depolarization of the neuromuscular junction . The elevation of intracranial pressure following succinylcholine administration has been observed in lightly anaesthetized patients and can be prevented by intravenous lidocaine , deep anaesthesia and a defasciculating dose of non-depolarizing muscle relaxants [40,41]. Moreover, some studies have failed to demonstrate any significant change in cerebral perfusion pressure, intracranial pressure and cortical electrical activity following administration of succinylcholine in ventilated head-injured patients [42,43]. It has also been reported that the influence of laryngoscopy and tracheal intubation on intracranial pressure far outweighs that of succinylcholine [42,44]. Consequently, although there are absolute contraindications to succinylcholine in anaesthetic practice, this drug should not be withheld in emergency airway situations because of intracranial pressure concerns . Another potential problem is that the upregulation of acetylcholine receptors may be responsible for potassium release and prolonged neuromuscular blockade after succinylcholine administration . After trauma, this increased sensitivity to succinylcholine may start about 3-4 days after denervation if sufficient muscle is affected, and reaches dangerous levels at 7-8 days . The upregulation phenomenon is considered more extensive when resulting from upper motor neuron lesions and trauma than when it occurs in response to chronic anticonvulsants . In addition, it has been reported recently that the primary cause of succinylcholine-induced hyperkaliaemia and cardiac arrest is acute rhabdomyolysis rather than upregulation .
Atracurium, cisatracurium, vecuronium and rocuronium are non-depolarizing muscle relaxants with an intermediate duration of action that can be used in neurosurgical anaesthesia. Cisatracurium administered as an intravenous bolus in ventilated adult neurosurgical patients has been shown to result in less cerebral and cardiovascular side-effects compared with an equipotent dose of atracurium . Vecuronium and rocuronium are devoid of any effect on intracranial pressure, cerebral perfusion pressure and mean arterial pressure in ventilated neurosurgical patients, although rocuronium may provoke a slight, clinically irrelevant increase in heart rate . The resistance phenomenon observed in denervation syndromes may concern all the non-depolarizing muscle relaxants regardless of their pharmacological family, but this resistance is variable in practice, depending on the degree of upregulation of acetylcholine receptors. In patients suffering from focal or hemispheric lesions, it is advised that one monitors neuromuscular function on the healthy side in order to assess appropriately the degree of muscle paralysis and to avoid overestimating drug requirements. The resistance to non-depolarizing muscle relaxants in patients receiving chronic anticonvulsant therapy has been observed with metocurine [30,50], pancuronium , vecuronium [33,52,53], doxacurium , pipecuronium [37,55] and rocuronium [56-59]. Atracurium has been reported to have a shorter duration of action in epileptic than in non-epileptic patients , while chronic carbamazepine therapy does not influence its onset time and duration of action . Regarding cisatracurium, it has been shown that onset and duration of neuromuscular blockade is not affected by anticonvulsant therapy but that speed of recovery is significantly faster . The resistance phenomenon appears to be less with atracurium and cisatracurium than with steroid non-depolarizing muscle relaxants, which would favour a pharmacokinetic mechanism. However, the explanation is probably not exclusively pharmacokinetic and the relative importance of contributing factors may differ according to the underlying pathology, the duration and type of anticonvulsant therapy, and the muscle relaxant involved including its own metabolism. What neuroanaesthesiologists must keep in mind is that the pharmacodynamics of all muscle relaxants may be substantially modified in neurosurgical patients and that appropriate monitoring of neuromuscular transmission is mandatory when assessing their effect accurately at the neuromuscular junction.
The use of muscle relaxants in neurosurgical anaesthesia is essentially governed by non-specific indications. If those agents may be helpful in certain situations, they may also be undesirable or even contraindicated in other circumstances, and sometimes inefficient at usual doses. The main benefits of muscle relaxants are to facilitate tracheal intubation and avoid consequences of coughing and movements on intracranial dynamics. If muscle relaxation may help to improve intracranial conditions, it does not dispense anaesthetists from providing appropriate anaesthesia and analgesia, which are determinant factors of brain relaxation. The benefit of muscle relaxants should be balanced against their potential exciting effects on the central nervous system as they do cross the blood-brain barrier under certain circumstances. The choice of a muscle relaxant for neurosurgical anaesthesia will depend on the reason warranting muscle relaxation. Except for emergency situations, the preference is given to non-depolarizing drugs of short or intermediate duration of action. The pharmacodynamic profile of these drugs may be modified in denervation syndromes and in patients under chronic anticonvulsant therapy. Those modifications support appropriate monitoring of neuromuscular transmission to avoid overestimating drugs requirements and to assess correctly their impact on neuromuscular function.
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