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Anesthesia and the Trigeminocardiac Reflex
C H A P T E R
13 Anesthesia and the Trigeminocardiac Reflex Keshav Goyal1 and Tumul Chowdhury2 1
Critical and Intensive Care, Department of Neuroanaesthesiology, JPNATC, All India Institute of Medical Sciences, New Delhi, India, 2 Neuroanesthesia, Department of Anesthesiology and Perioperative Medicine, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada O U T L I N E Introduction 154
Inhalational Anesthetic Agents
Mechanism and Types of the TCR
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Ketamine 162
Perioperative Variables Surgical Factors
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Other Drugs
Location 156 Anatomical Areas, Step of Procedure 156 Type, Frequency and Intensity of the Stimulus 158
Physiological Variables
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Other Situations Mimicking the TCR
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Anesthetic Agents
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Local Anesthetics
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Anticholinergics 161 Narcotics 161
Trigeminocardiac Reflex. DOI: http://dx.doi.org/10.1016/B978-0-12-800421-0.00013-8
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Cannabinoids 162 Tonabersat 162 Anesthetic Depth
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Anesthetic Management of the TCR
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Postoperative Functional Consequences of Intraoperative Occurrences of the TCR 163 Future Research
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Conclusion 164 References 164
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© 2012 2015 Elsevier Inc. All rights reserved.
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INTRODUCTION The trigeminocardiac reflex (TCR) is a brain stem reflex that mediates through two different cranial nerves. The trigeminal nerve forms the afferent limb, and the vagus nerve constitutes the efferent one. Unique manifestations of this reflex include a depressive effect both in hemodynamic variables and on respiration upon stimulation of any sensory branch of the fifth nerve.1–17 Interestingly, most of the research related to TCR events was carried out by neuroscientists (Schaller et al., Kumada et al., etc.); however, the term “TCR” was coined by an anesthesiologist (Shelly et al.). Importantly, the anesthesiologist is the person in the operating room who first observes TCR events and who informs the surgical team of their appearance. Moreover, the TCR is not limited to neurosurgical procedures: it also has been linked to various other surgical interventions and procedures, including maxillofacial, ocular, nasal, and dental surgeries. Therefore, anesthesiologists require a thorough knowledge of the TCR and related phenomena. Still, it is a well-known fact that surgical procedures and related events influence the occurrence of the TCR, even though the role of anesthesia-related factors is yet not fully understood.18–23 Such factors, including the type of anesthetic agents, the depth of anesthesia, and other perioperative variables, may influence the occurrence of TCR episodes, yet very few reports highlight this issue as a whole. Therefore, this chapter offers an in-depth insight into anesthesia-related influences on TCR events.
MECHANISM AND TYPES OF THE TCR Because anesthesia-related variables have important interactions on TCR pathways, including afferent limbs, nuclei, efferent limbs, and various receptors, it is imperative for anesthesiologists to understand the mechanism of the TCR. Any kind of stimulus (mechanical, electrical, chemical, or thermal) can incite a TCR episode.1 Abrupt, sustained traction is more reflexogenic than smooth, gentle traction during surgery.24 Whatever the stimulus, it is carried by the sensory divisions of the trigeminal nerve and constitutes an afferent pathway. The efferent limb is constituted via the tenth cranial nerve and is responsible for clinical manifestations of the TCR. (A detailed description of the anatomical pathways of the reflex is given in a separate chapter.) It is also important to understand the different types of TCR and their related manifestations. Schaller et al.1 have done extensive work on the classification of different subtypes, which are divided mainly into the central TCR and the peripheral TCR on the basis of anatomical pathways. The functional hemodynamic manifestations of these subtypes range from hypotension to hypertension.1,25 Following is a description of the two main types of TCR: 1. The central (proximal) reflex. This type of TCR is produced by stimulation of the trigeminal nerve anywhere along the path from the Gasserian ganglion to the brain stem. It usually presents as severe bradycardia and hypotension. The majority of TCR literature on brain matter handling in various neurosurgical procedures consists of examples of the central TCR.
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2. The peripheral (distal) reflex. This type of TCR is produced by stimulation of the trigeminal nerve outside the cranium (the path from the peripheral branches to the Gasserian ganglion). The peripheral TCR is subdivided into (i) the oculocardiac reflex (OCR), (ii) the maxillomandibulocardiac reflex, and (iii) the diving reflex. Other types of TCR also have been described, including a dentocardiac reflex and a nasotrigeminal reflex; however, they constitute part of the maxillomandibular type of TCR. Finally, note that Chowdhury et al.25 recently suggested a new subtype of TCR known as the Gasserian ganglion TCR. This type of TCR is seen in various trigeminal neuralgia–related ablative procedures. Interestingly, all these subtypes of the TCR are mediated by different sensory branches of a single nerve (the trigeminal nerve). The peripheral TCR usually manifests as bradycardia with or without hypotension, whereas the central TCR presents with severe hypotension along with bradycardia. Whether or not the different forms of TCR may coexist in a single case is a matter of great curiosity, but Chowdhury et al. have reported that they can coexist in a single patient and can be hazardous if not properly taken care of during the intraoperative period.25 In that report, the influence of anesthetic depth and related factors on the occurrence of TCR episodes was highlighted.
PERIOPERATIVE VARIABLES Perioperative variables have some influence on the occurrence of the TCR;26–30 however, little work has been done to explore these variables. Importantly, several risk factors that increase the chances of inciting an episode of the OCR have been known for a couple of decades. Studies pertaining to the risk factors for OCR episodes were carried out, but unfortunately, little knowledge exists about other types of TCR; indeed, whatever knowledge that does exist is hypothesized mainly from the OCR studies. Because the OCR is a subtype of TCR (all subtypes of TCR are mediated by the same nerve), it can be assumed that factors similar to those related to the risk of inciting an episode of the OCR also potentiate the risk of eliciting the TCR in general (Table 13.1). TABLE 13.1 Various Risk Factors Known to Potentiate TCR Surgical Factors (Location and Step of Procedure)1,31,32 Type, frequency, and intensity of stimulus (abrupt and sustained traction and surgical division of nerve) Hypercapnia ● Hypoxemia ● Acidosis ● Hypotension ● Age (more intense in children) ● Level of anesthesia (light anesthesia has more risk) ● Drugs: ● Narcotics ● Propofol ● Calcium channel blockers ● Beta-blockers. ● ●
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Surgical Factors It is also important for anesthesiologists to know about various surgical factors, including the type of procedure undertaken, the step of the procedure, and the pathology involved (size of tumor, invasiveness, etc.), all of which influence the occurrence of the TCR. Location Among various surgical factors, the most important remains the anatomical location of the surgical procedure or type of procedure. Certain surgical procedures have been more commonly associated with TCR phenomena. Rhinoplasty, skull-base surgeries such as transsphenoidal and transnasal surgeries, cerebellopontine angle surgeries, microvascular decompression, ablative procedures for trigeminal neuralgia, skin flap elevation in craniotomy, various craniofacial surgeries, maxillofacial surgery (especially bilateral sagittal split ramus osteotomy), and blepharoplasties are some of the common surgeries known to be associated with an increased incidence of TCR episodes.33–35 The incidence of TCR in different types of surgery has been reported in various studies, beginning with the lowest incidence, 1.6–1.8% in maxillofacial surgeries, and moving on to 7.5–10% in transsphenoidal surgeries, 8–9% in rhinoplasty, 11% in cerebellopontine angle surgeries, and around 18% in microvascular decompression for trigeminal neuralgia. Ablative procedures for trigeminal neuralgia impose the highest incidence (up to 90%) of TCR episodes.14,18,36–39 The high incidence in these procedures may be due to surgical manipulation and direct stimulation of the trigeminal nerve and its related ganglion. The intraoperative TCR during transsphenoidal pituitary surgery is more likely with invasive pituitary adenomas, which extend outside the pituitary fossa.8,40,41 One therefore has to be vigilant regarding potential episodes of the TCR when these surgeries are being planned (Table 13.2). Cranial neurosurgical procedures have a variable association with the TCR. Recent prospective studies to determine TCR incidence in 190 patients undergoing standard general anesthesia for surgery of supratentorial, infratentorial, and skull-base lesions report four patients—two male and two female—who experienced TCR episodes intraoperatively (incidence: 2.1%).14 Three additional patients had a TCR episode just at the end of their operation when the skin sutures were being applied, while in the other cases an episode of the TCR occurred when a brain tumor sample was being taken from just below the lateral wall of the cavernous sinus. Anatomical Areas, Step of Procedure It is important to be extra vigilant during certain steps of surgical procedures, especially during the manipulation of certain anatomical areas because handling those areas may provoke intense TCR episodes. Manipulation on or just beneath the lateral wall of the cavernous sinus (near the central course of the trigeminal nerve) has been associated with triggering TCR episodes.42 Accordingly, to prevent the TCR from occurring, surgeons should alert anesthesiologists before starting to work around the area of lateral wall of the cavernous sinus. Similarly, dural handling has been reported to incite TCR episodes and should therefore be carefully monitored. The preparation of nasal mucosae and the sinus ethmoidalis during nasal procedures, including transsphenoidal pituitary surgeries and paranasal sinus operations, has resulted
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TABLE 13.2 Surgeries Commonly Associated with Episodes of the TCR1 Skull-base neurosurgery Transsphenoidal and transnasal pituitary surgeries Cerebellopontine angle surgeries Cavernous sinus surgeries Microvascular decompression for trigeminal neuralgia Balloon compression rhizotomy of the trigeminal ganglion Skin flap elevation in craniotomy Craniofacial surgeries Osteotomies Soft-tissue manipulation in the region innervated by the trigeminal nerve Le Fort I osteotomy Midface fracture reduction Elevation of complex zygomatic fractures Distraction or insufflation of the temporomandibular joint Craniofacial pain surgery Orofacial surgeries Rhinoplasty Maxillofacial surgeries, especially bilateral sagittal split ramus osteotomy Mechanical stimulation of the ocular and periocular structures (strabismus surgery, etc.) Blepharoplasties
in bradycardia that progresses to transient asystole and hypotension, probably because of the direct stimulation of the ethmoidal nerve.43 The parabrachial nucleus and the KöllikerFuse nucleus play a pivotal role in the mediation and maintenance of such autonomic responses induced by the (maxillomandibular) nasotrigeminal reflex, a subtype of the TCR.8,13,44–46 Similarly, stimulation of the sensory branch of the trigeminal nerve in the columellar area in rhinoplasty has been reported to provoke TCR episodes, even under general anesthesia.33 Abrupt and sustained surgical stretching or manipulation, as well as direct stimulation of the trigeminal nerve, can provoke an intense TCR compared with smooth and gentle traction and so should be avoided.24 In cases of ablative procedures for trigeminal neuralgia, insertion of the needle may produce bradycardia and hypotension, but those events may be vasovagal responses rather than a TCR phenomenon. TCR events have been noted during ablative stimuli (chemical, electrical/thermal, mechanical). Among all of the possibilities, the balloon decompression step is most capable of inciting intense TCR episodes that may manifest variably, including bradycardia/asystole, arrhythmias, hypertension, and tachycardia.47 In some medical centers, anticholinergic agents are administered routinely before the actual decompression procedure begins.
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In craniotomies, TCR episodes can be provoked during a number of different steps, including scalp nerve block, skull pin fixation, skin flap elevation, dural opening, tumor handling at or near the vicinity of the trigeminal nerve, dural closure, and even skin closure. Again, anesthesiologists should be extra vigilant during these neurosurgical steps. Type, Frequency and Intensity of the Stimulus Traction, or abrupt stretching, of the nerve is the factor that is most capable of inciting TCR episodes.24 In general, the intensity of an episode is directly proportional to the strength of the stimulus. Therefore, the greater the traction at or near the nerve, the greater will be the chance of a TCR event. This relationship holds for the majority of TCR episodes reported in the literature; however, recent reports by Chowdhury et al. highlighted the fact that even mild traction of the skin may provoke a highly potent TCR event. Therefore, other factors also regulate the intensity of TCR phenomena in certain situations. Similarly, in general, mechanical stimuli, such as stretch, seem to be the most powerful provoking factors; however, chemical, thermal, and electrical stimuli have also been found to incite TCR events.
Physiological Variables If we know the various risk factors for the TCR, we can try and prevent the reflex from occurring by avoiding these factors. Physiological risk factors have been shown to be important in relation to the TCR. In this regard, many studies of the OCR, a subtype of the TCR, have implicated several physiological variables, including hypercapnia, hypoxemia, acidosis, age (more common in children), light anesthesia, and drugs, such as narcotics, propofol, calcium channel blockers, and beta-blockers.48 Although there are no direct studies of risk factors for the TCR, factors affecting the OCR can be considered to affect the TCR as well. Potent, rapidly acting narcotics may augment the vagal tone and can potentiate the reflex by inhibiting the sympathetic nervous system.24,28,48–51 Beta-blockers also potentiate a vagal response by reducing the sympathetic activity of the heart. Calcium channel blockers act by peripheral arterial smooth muscle relaxation, causing vasodilation that leads to hypotension.52 Manipulation of any of the branches of the trigeminal nerve leads to potentiation of these drugs and a worsening of the vagal effect.
OTHER SITUATIONS MIMICKING THE TCR Bradycardia and hypotension episodes similar to those which occur with the TCR can also occur with other reflexes, such as a vasovagal reflex, which can be induced by pain, hypovolemia, and panic.53–55 A loud, horrible sound, a fearful scene, or an unpleasant smell can frighten an awake patient and may provoke a vasovagal reflex during a surgical procedure in the vicinity of the trigeminal nerve.
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ANESTHETIC AGENTS The TCR is one of the autonomic reflexes in human beings and is thought to be phylogenetically similar to the protective diving reflex in birds and amphibians.42 Indeed, the TCR may have a protective role in human beings, but still, the reflex can be catastrophic, and bradycardia can progress to asystole and even, occasionally, death.27,47,56,57 One of the main features of balanced and safe anesthesia is that it should blunt the autonomic reflexes, so, as with any other autonomic reflexes, the TCR is controlled to ensure the safety of patients. Different anesthetic agents can modulate the TCR differently, some dampening the reflex and some amplifying the response. The TCR occurs less commonly with sevoflurane and desflurane compared with halothane, ketamine is associated with a decreased incidence of the reflex compared with propofol, and sevoflurane has a lower incidence than both halothane and propofol, while fast-acting opioids exaggerate the OCR and thus very likely the TCR.58–65 Amplification of the response can have some very serious consequences. It is interesting to know the various mechanisms by which different anesthetic agents modulate the TCR differently, because such knowledge can be helpful in reducing the incidence of the TCR and may increase safety for patients. Anesthetics can alter the TCR at many sites within the brain stem circuitry, including (1) the primary afferent pathway (the sensory nerve endings of the trigeminal nerve via the Gasserian ganglion to the trigeminal nucleus) that synapses upon neurons in the sensory trigeminal nucleus and (2) secondorder neurons to the efferent cholinergic cardioinhibitory neurons in the nucleus ambiguus, by acting on the synaptic neurotransmission at either presynaptic or postsynaptic sites.66 Second-order neurons in the trigeminal nucleus have been identified as glutamatergic by both pharmacological and immunohistochemistry methods.67,68 In a study by Wang et al., the stimulation of trigeminal nerve endings was shown to evoke excitatory postsynaptic currents (EPSCs) that activate postsynaptic N-methyl-daspartate (NMDA) receptors as well as non-NMDA receptors. NMDA receptors were found to be responsible for a slow component (with a long decay phase) and were blocked by the selective NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP-5). Non-NMDA receptor activation was shown to evoke a fast and large EPSC current response that was completely blocked by the selective AMPA/kainate receptor antagonist 6-cyano-7-nitroguinoxaline-2,3-dione. AMPA/kainate and NMDA glutamatergic receptor antagonists together could completely block stimulation-evoked EPSCs.19 In this study, the latency and conduction velocity of the stimulation-evoked EPSCs in either the trigeminal sensory nucleus or efferent parasympathetic cardiac neurons was not changed significantly by the anesthetic drugs (ketamine, propofol, isoflurane, and fentanyl) that were tested. The EPSCs’ peak amplitude and area showed a varied synaptic response to the different drugs.19 Neurotransmission in afferent limbs (via trigeminal sensory neurons in the spinal trigeminal nucleus) and efferent limbs (via polysynaptic pathways to premotor parasympathetic cardiac neurons in the nucleus ambiguus) is mediated by glutamatergic pathways, thereby activating both the NMDA and AMPA/kainate receptors at both sites. The sensory trigeminal nuclei receive inhibitory GABAergic, glycinergic, and excitatory glutamatergic neurotransmission.68–70 The combined anatomical, electrophysiological, and pharmacological analysis carried
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out in studies indicates that spinal trigeminal neurons are coupled to the TCR afferent pathway via direct, monosynaptic excitatory glutamatergic synapses activating both the NMDA and AMPA/kainate receptors in the trigeminal nucleus. At the same time, the neurotransmission in the parasympathetic cardiac neurons in the nucleus ambiguus, which are related to the TCR efferent pathway, is mediated by polysynaptic pathways. Apart from possessing glutamatergic pathways, these neurons also have excitatory serotonergic and muscarinic acetyl cholinergic pathways involved in the modulation of the TCR.71,72 In the Wang et al. study, ketamine probably inhibited both the NMDA and AMPA/kainate receptor-mediated synaptic responses in the afferent and efferent pathways while isoflurane and fentanyl did not have any effect on the afferent pathway, but synaptic transmission of the efferent pathway was inhibited by isoflurane yet was enhanced by fentanyl.19 Either isoflurane and fentanyl act on receptors that are more densely located near the synapses surrounding cholinergic cardiac neurons, or the subunit composition of these receptors are more readily modulated by these agents than are receptors that are involved in the neurotransmission at the afferent pathway.19 Most likely, NMDA receptors are responsible for the inhibition of responses in the cases of ketamine and isoflurane at the efferent pathway. Isoflurane is likely to inhibit the NMDA receptors in the efferent pathway, but not in the afferent pathway, of the trigeminal nucleus. Isoflurane significantly inhibited the amplitude of evoked EPSCs at efferent neurons but not at afferent ones. The disparate responses at the two sites may be related to the different sensitivity, or selectivity, of the receptors involved in glutamatergic neurotransmission at these sites. NMDA receptors are tetramers composed of two NR1 and two NR2 subunits, which bind glycine and glutamate, respectively. Isoflurane is reported to be a competitive antagonist at the NMDA receptor glycine-binding site.73 Isoflurane is also reported to depress inhibitory GABAergic neurotransmission that takes place through endogenous nicotinic receptors to the parasympathetic cardiac neurons.74 Thus, smoking is associated with a greater likelihood of occurrence of the TCR. Many of the anesthetic agents act as NMDA antagonists. Ketamine is a prototype of a noncompetitive NMDA antagonist. It antagonizes NMDA receptors by both open-channel and closed-channel blockade and is in turn associated with a decreased frequency of opening. Ketamine has a high specific selectivity for glutamatergic neurons. Because it decreases the duration of evoked potentials in both afferent and efferent pathways, ketamine anesthesia is associated with a reduced TCR incidence and intensity during surgeries involving trigeminal nerve stimulation. Fentanyl most likely acts via the stimulation of µ-opioid receptors to enhance glutamate release and/or postsynaptic glutamate receptor activation. Anesthetics and narcotics act mainly at the level of sensory receptors within the spinal cord and sometimes at the level of the cerebral cortex.42 Thus, electrical impulses can be transferred through nerve fiber even when the patient has been administered a deep level of general anesthesia.
LOCAL ANESTHETICS Local anesthetics, such as lignocaine, block sodium channels and, thereby, nerve conduction. Unlike general anesthetics, which act on sensory receptors, thus sparing the TRIGEMINOCARDIAC REFLEX
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neurotransmission of electrical impulses through the nerve fiber, local anesthetics block the electrical transmission, ultimately cutting off the reflex arc. As a result, local anesthetics might help abort the TCR in spite of the failure to relieve it by anticholinergics. Some studies report that prophylaxis of TCR can be better achieved with local anesthetic infiltration or nerve block.75–77 Apart from reducing the incidence of the reflex, its severity is also decreased after the block. Misurya et al. reported that both atropine and retrobulbar block by local anesthetic reduced the OCR rate by 10–20%, but when both were used together, the OCR could be completely suppressed.77 Some reports indicate that a peripheral TCR can still be evoked even when a block, such as scalp block, is administered.78 One report advocates the application of a local anesthetic at the root entry zone of the trigeminal nerve, but local anesthetics can themselves precipitate bradycardia and hypotension (as, e.g., in the preparation of a columellar area in rhinoplasty).33
ANTICHOLINERGICS Anticholinergic prophylaxis has been reported to decrease the incidence of OCRs.79–81 However, atropine may cause bigeminy and increase ectopic beats, and these arrhythmias are more persistent than the OCR.82 Moreover, recent studies report that atropine is not universally as effective as OCR prophylaxis, and it is even said to be ineffective in the usual intramuscular premedication doses.83,84
NARCOTICS Fast-acting opioids (fentanyl, sufentanil, and remifentanil) have been reported to show an exaggerated response of the OCR. Arnold et al. reported that rapidly acting opioids enhance OCRs that are elicited by extraocular muscle tension during strabismus surgery.63 Remifentanil can cause bradycardia either by parasympathetic activation or by direct negative chronotropic effects.85 In one study, a group that received ketamine and remifentanil had more OCR incidences than a group that was administered ketamine and sevoflurane, and similarly, a group that was given midazolam and remifentanil had more OCR episodes than a group that received midazolam and sevoflurane.64 Morphine has been reported to inhibit the TCR, provided that the spinal cord is intact—a finding suggesting that at least part of the action of systemic morphine is due to activation of descending inhibition.
INHALATIONAL ANESTHETIC AGENTS The major influence on the incidence of the TCR may be due to the vagolytic effect of inhalational agents: the less the vagal activity, the less is the incidence of the TCR. Cardiac vagal activity, measured by variability of the heart rate, has been reported to be least with desflurane and sevoflurane, intermediate with isoflurane and enflurane, and greatest with halothane.86 TRIGEMINOCARDIAC REFLEX
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OCR incidence has been found to be no different between desflurane and sevoflurane anesthesia.59 Thus, both agents can be safely used.
KETAMINE Ketamine has been associated with a decreased incidence of the OCR compared with propofol. Both a single bolus and continuous infusion of ketamine have been reported to reduce OCR incidence.61,62 Ketamine’s action may be due to sympathomimetic effects and inhibition of the parasympathetic reflex, whereas propofol increases bradycardia through a central sympatholytic effect and vagal stimulation.87,88 Hahnenkamp et al. reported that the incidence of the OCR was lowest with the continuous infusion of ketamine, compared with sevoflurane, halothane, and propofol, in that order.59,61
OTHER DRUGS Onyx (dimethylsulfoxide) is a liquid embolic system used for presurgical embolization in neurosurgery. Injection of this material into vessels in close proximity to the trigeminal nerve or its branches has been reported to evoke a vagal response from the TCR.89 To avoid catastrophic complications, authors have advised either pretreatment with anticholinergic drugs or the prophylactic placement of a transvenous pacemaker.
CANNABINOIDS Cannabinoid agonists (HU 210) have been reported to inhibit trigeminal withdrawal reflexes.90 Trigeminal and spinal reflexes are sensitive to these agonists if the spinal cord is intact. Part of their action appears to be due to the activation of descending inhibition.
TONABERSAT Tonabersat (SB-220453), a novel benzopyran with anticonvulsant properties, has been shown to attenuate trigeminal nerve–induced neurovascular reflexes.91 Tonabersat, carabersat, and other anticonvulsants could block trigeminal parasympathetic reflexes; therefore, these agents may have a therapeutic benefit under conditions that are likely to incite those reflexes.
ANESTHETIC DEPTH Anesthetic depth has been reported to affect the incidence of the TCR. A bispectral index (BIS) of 40–50 in pediatric patients under general anesthesia led to a significant decrease in the incidence of the OCR.30 In deeply anesthetized animals, an algesic stimulus is unable to determine whether there are any cardiorespiratory effects as a result of various reflexes. TRIGEMINOCARDIAC REFLEX
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ANESTHETIC MANAGEMENT OF THE TCR Manipulation of the trigeminal nerve and its branches may cause an episode of the TCR even if anticholinergic drugs are used.92 The cessation of stretching, manipulation, and/or stimulation forms the most important part of treatment. The most important intervention for managing the TCR is to pay proper attention to its potential danger and minimize any mechanical stimulation of the nerve. Identifying and, if possible, modifying risk factors, as well as administering prophylactic treatment with either vagolytic agents or peripheral nerve blocks in case of peripheral manipulation of the trigeminal nerve, should be undertaken. Meticulous, vigilant monitoring intraoperatively under anesthesia is a must. In case the reflex still occurs, manipulation of the nerve should cease and vagolytic agents should be administered. Continuous, and especially repeated, episodes of the TCR necessitate the administration of a high dose of an anticholinergic, preferably atropine. If the episode is still not resolved, even adrenaline may be prescribed.48
POSTOPERATIVE FUNCTIONAL CONSEQUENCES OF INTRAOPERATIVE OCCURRENCES OF THE TCR The occurrence of the TCR in the intraoperative period has been associated with a poor outcome. Patients operated on for vestibular schwannomas have had their hearing affected by the occurrence of the TCR intraoperatively.6,40 Gharabaghi et al. reported that hearing was preserved in just 11.1% of patients in a group that had experienced the TCR intraoperatively, compared with a much better 51.4% in a group that had not experienced the reflex; overall, hearing was preserved in 47% of the patients.40 Schaller et al. compared the occurrence and incidence of tinnitus in patients who did and did not have an intraoperative TCR episode.6 Seventeen percent of patients in the non-TCR group had ipsilateral tinnitus postoperatively, compared with up to 60% of the patients in the TCR group. The mechanisms behind increased hearing loss and tinnitus after the TCR are not clear, but it is assumed that intraoperative hypotension initiated by the reflex might be the principal cause. One of the things learned from the anesthetist’s side of these important observations is that it is no longer only the (neuro)surgeon`s skills that substantially influence the postoperative functional outcome, but also the intraoperative changes in vital parameters that are supervised by the (neuro) anesthetists. Such observations further underline the importance of the TCR away from being viewed as a simple intraoperative phenomenon to one of, if not the, principal intraoperative complications that have to be avoided. In such a context, further future research is needed.
FUTURE RESEARCH Anesthesia-related factors have been found to influence TCR events;93,94 however, randomized controlled trials should be conducted to explore this tentative hypothesis. Anesthetic depth–related influences on TCR episodes also need to be addressed in future studies. Differential features of vasovagal and TCR episodes need to be investigated, including whether there is any overlap between the pathways that play a role in inciting either kind of episode. Preventing TCR episodes is another area that requires further attention. TRIGEMINOCARDIAC REFLEX
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The last few years have seen a better understanding of the role and importance of the TCR, and that understanding has influenced anesthesiological research in such a way that a knowledge of the vital parameters involved has once again become important.
CONCLUSION Anesthesiologists have a very important role in the prevention, recognition, and treatment of the TCR, whose occurrence is associated with poor and, sometimes, life-threatening outcomes. The various risk factors (patient related, technique related, procedure related, and drug related) need to be assessed, and proper prophylactic measures undertaken, to avoid occurrences of the TCR. Sustained, abrupt traction of the trigeminal nerve must be avoided, and gentle manipulation, if at all required, applied to prevent episodes of the TCR. Various anesthetic and analgesic drugs, at clinically relevant concentrations, regulate the receptors at each site within the TCR reflex arc, and, if possible, anesthetic technique can be modified to prevent the TCR from occurring. Monitoring the depth of anesthesia (via, e.g., the BIS and the cerebral state index) and maintaining an adequate depth are advised.
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15. Schaller BJ. Ketamine and decrease of oculocardiac reflex. Acta Anaesthesiol Scand. 2008;52:446. 16. Prabhakar H, Ali Z, Rath GP. Trigemino-cardiac trigeminocardiac reflex may be refractory to conventional management in adults. Acta Neurochir (Wien). 2008;150:509–510. 17. Prabhakar H, Anand N, Chouhan RS, et al. Sudden asystole during surgery in the cerebellopontine angle. Acta Neurochir (Wien). 2006;148:699–700. 18. Schaller BJ, Probst R, Strebel S, Gratzl O. Trigemino-cardiac reflex during surgery in the cerebellopontine angle. J Neurosurg. 1999;90:215–220. 19. Wang X, Gorini C, Sharp D, Bateman R, Mendelowitz D. Anaesthetics differentially modulate the trigeminocardiac reflex excitatory synaptic pathway in the brainstem. J Physiol. 2011;589:5431–5442. 20. Kratschmer F. Influences of reflexes of the nasal mucosa on breathing and circulatory. Sber Akad Wis Wien. 1870;62:147–170. 21. Bainton R, Lizi E. Cardiac asystole complicating zygomatic arch fracture. Oral Surg Oral Med Oral Pathol. 1987;64:24–25. 22. Kontos HA. Regulation of the cerebral microcirculation in hypoxia and ischemia. In: Bryan-Brown CW, Ayres SM, eds. Oxygen Transport and Utilization. Fullerton, CA: Society of Critical Care Medicine; 1987:311–317. 23. Panneton WM, McCulloch PF, Sun W. Trigemino-autonomic connections in the muskrat: the neural substrate for the diving response. Brain Res. 2000;874:48–65. 24. Blanc VF, Hardy JF, Milot J, et al. The oculo-cardiac reflex: a graphic and statistical analysis in infants and children. Can Anaesth Soc J. 1983;30:360–369. 25. Chowdhury T, Cappellani RB, West M. Recurrent bradycardia and asystole in a patient undergoing supratentorial tumor resection: different types of trigeminal cardiac reflex in same patients.. Saudi J Anaesth. 2013;7(2):216–218. 26. Goerlich TM, Foja C, Olthoff D. Effects of sevoflurane versus propofol on oculocardiac reflex: a comparative study in 180 children. Anaesthesiol Reanim. 2000;25:17–21. 27. Lynch MJ, Parker H. Forensic aspects of ocular injury. Am J Forensic Med Pathol. 2000;21:124–126. 15. 28. Rivard JC, Lebowitz PW. Bradycardia after alfentanil-succinylcholine. Anesth Analg. 1988;76:907. 29. Safavi MR, Honarmand A. Comparative effects of different anesthetic regimens on the oculocardiac reflex. Iran Cardiovasc Res J. 2007;1:98–102. 30. Yi C, Jee D. Influence of the anaesthetic depth on the inhibition of the oculocardiac reflex during sevoflurane anaesthesia for paediatric strabismus surgery. Br J Anaesth. 2008;101(2):234–238. 31. Chowdhury T, Sandu N, Meuwly C, Cappellani RB, Schaller B. Trigeminal cardiac reflex: differential behavior and risk factors around the course of the trigeminal nerve. Future Neurol. 2014;9:41–47. 32. Chowdhury T, Sandu N, Meuwly C, Schaller B. Trigeminal cardiac reflex: current trends. Expert Rev Cardiovasc Ther. 2014;12(1):9–11. 33. Ozçelik D, Toplu G, Türkseven A, Sezen G, Ankarali H. The importance of the trigeminal cardiac reflex in rhinoplasty surgery. Ann Plast Surg. 2013 [Epub ahead of print]. 34. Prabhakar H, Rath GP, Arora R. Sudden cardiac standstill during skin flap elevation in a patient undergoing craniotomy. J Neurosurg Anesthesiol. 2007;19(3):203–204. 35. Rippmann V, Scholz T, Hellmann S, Amini P, Spilker G. The oculocardiac reflex in blepharoplasties. Handchir Mikrochir Plast Chir. 2008;40(4):267–271. 36. Precious DS, Skulsky FG. Cardiac dysrhythmias complicating maxillofacial surgery. Int J Oral Maxillofac Surg. 1990;19:279–282. 37. Filis A, Schaller B, Buchfelder M. Trigeminocardiac reflex in pituitary surgery. A prospective pilot study. Nervenarzt. 2008;79:669–675. 38. Yorgancilar E, Gun R, Yildirim M, Bakir S, Akkus Z, Topcu I. Determination of trigeminocardiac reflex during rhinoplasty. Int J Oral Maxillofac Surg. 2012;41:389–393. 39. Alexander JP. Reflex disturbances of cardiac rhythm during ophthalmic surgery. Br J Ophthalmol. 1975;59:518–524. 40. Gharabaghi A, Koerbel A, Samii A, et al. The impact of hypotension due to the trigeminocardiac reflex on auditory function in vestibular schwannoma surgery. J Neurosurg. 2006;104:369–375. 41. Campbell R, Rodrijo D, Cheung L. Asystole and bradycardia during maxillofacial surgery. Anesth Prog. 1994;41:13–16. 42. Etezadi F, Orandi AA, Orandi AH, et al. Trigeminocardiac reflex in neurosurgical practice: an observational prospective study. Surg Neurol Int. 2013;4:116. 43. Schipke JD, Cleveland S, Caspers C. Computer-assisted paranasal sinus operation induces diving bradycardia. Am J Otolaryngol. 2013;34(4):353–354.
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44. Kitabayashi M, Nakamura K, Murata T. A case of trigeminocardiac reflex in the pterional approach. No Shinkei Geka. 2012;40(10):903–907. 45. Panneton WM, Gan Q, Sun DW. Persistence of the nasotrigeminal reflex after pontomedullary transection. Respir Physiol Neurobiol. 2012;180(2-3):230–236. 46. Dutschmann M, Herbert H. Fos expression in the rat parabrachial and Kölliker-Fuse nuclei after electrical stimulation of the trigeminal ethmoidal nerve and water stimulation of the nasal mucosa. Exp Brain Res. 1997;117(1):97–110. 47. Schaller B, Graf R. Cerebral ischemic preconditioning: an experimental phenomenon or clinical important entity of stroke prevention? J Neurol. 2002;11:1503–1511. 48. Arasho B, Sandu N, Spiriev T, Prabhakar H, Schaller B. Management of the trigeminocardiac reflex: facts and own experience. Neurol India. 2009;57:375–380. 49. Starr NJ, Sethna DH, Estafanos FG. Bradycardia and asystole following rapid administration of sufentanil with vecuronium. Anesthesiology. 1986;64:521–523. 50. Lang S, Lanigan DT, van der Wal M. Trigeminocardiac reflexes: maxillary and mandibular variants of the oculocardiac reflex. Can J Anaesth. 1991;38:757–760. 51. Moonie GT, Ress EL, Elton D. The oculocardiac reflex during strabismus surgery. Can Anaesthet Soc J. 1964;11:621. 52. Schmeling WT, Kampine JP, Warltier DC. Negative chronotropic actions of sufentanil and vecuronium in chronically instrumented dogs pretreated with propanolol and/or diltiazem. Anesth Analg. 1989;66:4–14. 53. Cicogna R, Bonomi FG, Curnis A, et al. Parapharyngeal space lesions syncope-syndrome. A newly proposed reflexogenic cardiovascular syndrome. Eur Heart J. 1993;14:1476–1483. 54. Ludbrook J. Vasodilator responses to acute blood loss. Aust N Z J Surg. 1987;57:511–513. 55. Radtke A, Popov K, Bronstein AM, Gresty MA. Evidence for a vestibulo-cardiac reflex in man. Lancet. 2000;356:736–737. 56. Fayon M, Gauthier M, Blanc VF, Ahronheim GA, Michaud J. Intraoperative cardiac arrest due to the oculocardiac reflex and subsequent death in a child with occult Epstein-Barr virus myocarditis. Anesthesiology. 1995;83:622–624. 57. Schaller BJ, Filis A, Buchfelder M. The trigemino-cardiac reflex: the solution of many unresolved problems in medicine? J Chin Clin Med. 2007;2:541–542. 58. Allison CE, De Lange JJ, Koole FD, Zuurmond WW, Ros HH, van Schagen NT. A comparison of the incidence of the oculocardiac and oculorespiratory reflexes during sevoflurane or halothane anesthesia for strabismus surgery in children. Anesth Analg. 2000;90:306–310. 59. Oh AY, Yun MJ, Kim HJ, Kim HS. Comparison of desflurane with sevoflurane for the incidence of oculocardiac reflex in children undergoing strabismus surgery. Br J Anaesth. 2007;99:262–265. 60. Choi SH, Lee SJ, Kim SH, et al. Single bolus of intravenous ketamine for anesthetic induction decreases oculocardiac reflex in children undergoing strabismus surgery. Acta Anaesthesiol Scand. 2007;51:759–762. 61. Hahnenkamp K, Honemann CW, Fischer LG, Durieux ME, Muehlendyck H, Braun U. Effect of different anaesthetic regimes on the oculocardiac reflex during paediatric strabismus surgery. Paediatr Anaesth. 2000;10:601–608. 62. Gurkan Y, Kilickan L, Toker K. Propofol-nitrous oxide versus sevoflurane-nitrous oxide for strabismus surgery in children. Pediatr Anaesth. 1999;9:495–499. 63. Arnold RW, Jensen PA, Kovtoun TA, Maurer SA, Schultz JA. The profound augmentation of the oculocardiac reflex by fast acting opioids. Binocul Vis Strabismus Q. 2004;19:215–222. 64. Chung CJ, Lee JM, Choi SR, Lee SC, Lee JH. Effect of remifentanil on oculocardiac reflex in paediatric strabismus surgery. Acta Anaesthesiol Scand. 2008;52:1273–1277. 65. Ghai B, Ram J, Makkar JK, Wig J, Kaushik S. Subtenon block compared to intravenous fentanyl for perioperative analgesia in pediatric cataract surgery. Anesth Analg. 2009;108:1132–1138. 66. Schaller B. Trigeminocardiac reflex. A clinical phenomenon or a new physiological entity? J Neurol. 2004;251:658–665. 67. McCulloch PF, Panneton WM. Fos immunohistochemical determination of brainstem neuronal activation in the muskrat after nasal stimulation. Neuroscience. 1997;78:913–925. 68. McCulloch PF, Paterson IA, West NH. An intact glutamatergic trigeminal pathway is essential for the cardiac response to simulated diving. Am J Physiol Regul Integr Comp Physiol. 1995;269:R669–R677. 69. Avendano C, Machin R, Bermejo PE, Lagares A. Neuron numbers in the sensory trigeminal nuclei of the rat: a GABA- and glycine-immunocytochemical and stereological analysis. J Comp Neurol. 2005;493:538–553. 70. McCulloch PF. Activation of the trigeminal medullary dorsal horn during voluntary diving in rats. Brain Res. 2005;1051:194–198.
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71. Gorini C, Jameson HS, Mendelowitz D. Serotonergic modulation of the trigeminocardiac reflex neurotransmission to cardiac vagal neurons in the nucleus ambiguus. J Neurophysiol. 2009;102:1443–1450. 72. Gorini C, Philbin K, Bateman R, Mendelowitz D. Endogenous inhibition of the trigeminally-evoked neurotransmission to cardiac vagal neurons by muscarinic acetylcholine receptor activation. J Neurophysiol. 2010;104:1841–1848. 73. Dickinson R, Peterson BK, Banks P, et al. Competitive inhibition at the glycine site of the N-methyl-d-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology. 2007;107:756–767. 74. Wang X. Nicotinic receptors partly mediate brainstem autonomic dysfunction evoked by the inhaled anesthetic isoflurane. Anesth Analg. 2009;108:134–141. 75. Shende D, Sadhasivam S, Madan R. Effects of peribulbar bupivacaine as an adjunct to general anesthesia on peri-operative outcome following retinal detachment surgery. Anaesthesia. 2000;55:970–975. 76. Gupta N, Kumar R, Kumar S, Sehgal R, Sharma KR. A prospective randomised double blind study to evaluate the effect of peribulbar block or topical application of local anesthesia combined with general anesthesia on intra-operative and postoperative complications during paediatric strabismus surgery. Anaesthesia. 2007;62:1110–1113. 77. Misurya VK, Singh SP, Kulshrestha VK. Prevention of oculocardiac reflex (O.C.R) during extraocular muscle surgery. Indian J Ophthalmol. 1990;38:85–87. 78. Chowdhury T, West M. Intraoperative asystole in a patient undergoing craniotomy under monitored anesthesia care: is it TCR? J Neurosurg Anesthesiol. 2013;25:92–93. 79. Tramer MR, Sansonetti A, Fuchs-Buder T, Rifat K. Oculocardiac reflex and postoperative vomiting in paediatric strabismus surgery. A randomised controlled trial comparing four anaesthetic techniques. Acta Anaesthesiol Scand. 1998;42:117–123. 80. Klockgether-Radke A, Demmel C, Braun U, Muhlendyck H. Emesis and the oculocardiac reflex. Drug prophylaxis with droperidol and atropine in children undergoing strabismus surgery. Anaesthesist. 1993;42:356–360. 81. Chisakuta AM, Mirakhur RK. Anticholinergic prophylaxis does not prevent emesis following strabismus surgery in children. Paediatr Anaesth. 1995;5:97–100. 82. Donlon JV. Anesthesia for eye, ear, nose, and throat surgery. In: Miller RD, ed. Anesthesia. Philadelphia, PA: Churchill Livingstone; 2005:2527–2531. 83. Cook-Sather SD. Ophthalmic problems and complications. In: Atlee JL, ed. Complications in Anesthesia. 2nd ed. Philadelphia, PA: Saunders; 2007:692–697. 84. McGoldrick KE, Gayer SI. Anesthesia and the eye. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006:974–996. 85. Tirel O, Chanavaz C, Bansard JY, et al. Effect of remifentanil with and without atropine on heart rate variability and RR interval in children. Anaesthesia. 2005;60:982–989. 86. Picker O, Scheeren TW, Arndt JO. Inhalational anaesthetics increases heart rate by decreasing cardiac vagal activity in dogs. Br J Anaesth. 2001;87:748–754. 87. Yamamura T, Kimura T, Furukawa K. Effects of halothane, thiamylal, and ketamine on central sympathetic and vagal tone. Anesth Analg. 1983;62:129–134. 88. Tramer MR, Moore RA, McQuay HJ. Propofol and bradycardia: causation, frequency and severity. Br J Anaesth. 1997;78:642–651. 89. Amiridze N, Darwish R. Hemodynamic instability during treatment of intracranial dural arteriovenous fistula and carotid cavernous fistula with onyx: preliminary results and anesthesia considerations. J Neurointerv Surg. 2009;1(2):146–150. 90. Jenkins S, Worthington M, Harris J, Clarke RW. Differential modulation of withdrawal reflexes by a cannabinoid in the rabbit. Brain Res. 2004;1012(1–2):146–153. 91. Parsons AA, Bingham S, Raval P, Read S, Thompson M, Upton N. Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reflexes. Br J Pharmacol. 2001;132(7):1549–1557. 92. Chigurupati K, Vemuri NN, Velivela SR, Mastan SS, Thotakura AK. Topical lidocaine to suppress trigeminocardiac reflex. Br J Anaesth. 2013;110(1):145. 93. Meuwly C, Golanov E, Chowdhury T, Erne P, Schaller B. Trigemincal cardiac reflex: new thinking model about the definition based on a literature review. Medicine (Baltimore). 2015;94:e484. 94. Chowdhury T, Mendelowitz D, Golanov E, et al. Trigeminocardiac reflex: the current clinical and physiological knowledge. J Neurosurg Anesthesiol. 2015;27:136–147.
TRIGEMINOCARDIAC REFLEX
13 Anesthesia and the Trigeminocardiac Reflex Keshav Goyal1 and Tumul Chowdhury2 1
Critical and Intensive Care, Department of Neuroanaesthesiology, JPNATC, All India Institute of Medical Sciences, New Delhi, India, 2 Neuroanesthesia, Department of Anesthesiology and Perioperative Medicine, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada O U T L I N E Introduction 154
Inhalational Anesthetic Agents
Mechanism and Types of the TCR
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Ketamine 162
Perioperative Variables Surgical Factors
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Other Drugs
Location 156 Anatomical Areas, Step of Procedure 156 Type, Frequency and Intensity of the Stimulus 158
Physiological Variables
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Other Situations Mimicking the TCR
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Anesthetic Agents
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Local Anesthetics
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Anticholinergics 161 Narcotics 161
Trigeminocardiac Reflex. DOI: http://dx.doi.org/10.1016/B978-0-12-800421-0.00013-8
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Cannabinoids 162 Tonabersat 162 Anesthetic Depth
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Anesthetic Management of the TCR
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Postoperative Functional Consequences of Intraoperative Occurrences of the TCR 163 Future Research
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Conclusion 164 References 164
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© 2012 2015 Elsevier Inc. All rights reserved.
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INTRODUCTION The trigeminocardiac reflex (TCR) is a brain stem reflex that mediates through two different cranial nerves. The trigeminal nerve forms the afferent limb, and the vagus nerve constitutes the efferent one. Unique manifestations of this reflex include a depressive effect both in hemodynamic variables and on respiration upon stimulation of any sensory branch of the fifth nerve.1–17 Interestingly, most of the research related to TCR events was carried out by neuroscientists (Schaller et al., Kumada et al., etc.); however, the term “TCR” was coined by an anesthesiologist (Shelly et al.). Importantly, the anesthesiologist is the person in the operating room who first observes TCR events and who informs the surgical team of their appearance. Moreover, the TCR is not limited to neurosurgical procedures: it also has been linked to various other surgical interventions and procedures, including maxillofacial, ocular, nasal, and dental surgeries. Therefore, anesthesiologists require a thorough knowledge of the TCR and related phenomena. Still, it is a well-known fact that surgical procedures and related events influence the occurrence of the TCR, even though the role of anesthesia-related factors is yet not fully understood.18–23 Such factors, including the type of anesthetic agents, the depth of anesthesia, and other perioperative variables, may influence the occurrence of TCR episodes, yet very few reports highlight this issue as a whole. Therefore, this chapter offers an in-depth insight into anesthesia-related influences on TCR events.
MECHANISM AND TYPES OF THE TCR Because anesthesia-related variables have important interactions on TCR pathways, including afferent limbs, nuclei, efferent limbs, and various receptors, it is imperative for anesthesiologists to understand the mechanism of the TCR. Any kind of stimulus (mechanical, electrical, chemical, or thermal) can incite a TCR episode.1 Abrupt, sustained traction is more reflexogenic than smooth, gentle traction during surgery.24 Whatever the stimulus, it is carried by the sensory divisions of the trigeminal nerve and constitutes an afferent pathway. The efferent limb is constituted via the tenth cranial nerve and is responsible for clinical manifestations of the TCR. (A detailed description of the anatomical pathways of the reflex is given in a separate chapter.) It is also important to understand the different types of TCR and their related manifestations. Schaller et al.1 have done extensive work on the classification of different subtypes, which are divided mainly into the central TCR and the peripheral TCR on the basis of anatomical pathways. The functional hemodynamic manifestations of these subtypes range from hypotension to hypertension.1,25 Following is a description of the two main types of TCR: 1. The central (proximal) reflex. This type of TCR is produced by stimulation of the trigeminal nerve anywhere along the path from the Gasserian ganglion to the brain stem. It usually presents as severe bradycardia and hypotension. The majority of TCR literature on brain matter handling in various neurosurgical procedures consists of examples of the central TCR.
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2. The peripheral (distal) reflex. This type of TCR is produced by stimulation of the trigeminal nerve outside the cranium (the path from the peripheral branches to the Gasserian ganglion). The peripheral TCR is subdivided into (i) the oculocardiac reflex (OCR), (ii) the maxillomandibulocardiac reflex, and (iii) the diving reflex. Other types of TCR also have been described, including a dentocardiac reflex and a nasotrigeminal reflex; however, they constitute part of the maxillomandibular type of TCR. Finally, note that Chowdhury et al.25 recently suggested a new subtype of TCR known as the Gasserian ganglion TCR. This type of TCR is seen in various trigeminal neuralgia–related ablative procedures. Interestingly, all these subtypes of the TCR are mediated by different sensory branches of a single nerve (the trigeminal nerve). The peripheral TCR usually manifests as bradycardia with or without hypotension, whereas the central TCR presents with severe hypotension along with bradycardia. Whether or not the different forms of TCR may coexist in a single case is a matter of great curiosity, but Chowdhury et al. have reported that they can coexist in a single patient and can be hazardous if not properly taken care of during the intraoperative period.25 In that report, the influence of anesthetic depth and related factors on the occurrence of TCR episodes was highlighted.
PERIOPERATIVE VARIABLES Perioperative variables have some influence on the occurrence of the TCR;26–30 however, little work has been done to explore these variables. Importantly, several risk factors that increase the chances of inciting an episode of the OCR have been known for a couple of decades. Studies pertaining to the risk factors for OCR episodes were carried out, but unfortunately, little knowledge exists about other types of TCR; indeed, whatever knowledge that does exist is hypothesized mainly from the OCR studies. Because the OCR is a subtype of TCR (all subtypes of TCR are mediated by the same nerve), it can be assumed that factors similar to those related to the risk of inciting an episode of the OCR also potentiate the risk of eliciting the TCR in general (Table 13.1). TABLE 13.1 Various Risk Factors Known to Potentiate TCR Surgical Factors (Location and Step of Procedure)1,31,32 Type, frequency, and intensity of stimulus (abrupt and sustained traction and surgical division of nerve) Hypercapnia ● Hypoxemia ● Acidosis ● Hypotension ● Age (more intense in children) ● Level of anesthesia (light anesthesia has more risk) ● Drugs: ● Narcotics ● Propofol ● Calcium channel blockers ● Beta-blockers. ● ●
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Surgical Factors It is also important for anesthesiologists to know about various surgical factors, including the type of procedure undertaken, the step of the procedure, and the pathology involved (size of tumor, invasiveness, etc.), all of which influence the occurrence of the TCR. Location Among various surgical factors, the most important remains the anatomical location of the surgical procedure or type of procedure. Certain surgical procedures have been more commonly associated with TCR phenomena. Rhinoplasty, skull-base surgeries such as transsphenoidal and transnasal surgeries, cerebellopontine angle surgeries, microvascular decompression, ablative procedures for trigeminal neuralgia, skin flap elevation in craniotomy, various craniofacial surgeries, maxillofacial surgery (especially bilateral sagittal split ramus osteotomy), and blepharoplasties are some of the common surgeries known to be associated with an increased incidence of TCR episodes.33–35 The incidence of TCR in different types of surgery has been reported in various studies, beginning with the lowest incidence, 1.6–1.8% in maxillofacial surgeries, and moving on to 7.5–10% in transsphenoidal surgeries, 8–9% in rhinoplasty, 11% in cerebellopontine angle surgeries, and around 18% in microvascular decompression for trigeminal neuralgia. Ablative procedures for trigeminal neuralgia impose the highest incidence (up to 90%) of TCR episodes.14,18,36–39 The high incidence in these procedures may be due to surgical manipulation and direct stimulation of the trigeminal nerve and its related ganglion. The intraoperative TCR during transsphenoidal pituitary surgery is more likely with invasive pituitary adenomas, which extend outside the pituitary fossa.8,40,41 One therefore has to be vigilant regarding potential episodes of the TCR when these surgeries are being planned (Table 13.2). Cranial neurosurgical procedures have a variable association with the TCR. Recent prospective studies to determine TCR incidence in 190 patients undergoing standard general anesthesia for surgery of supratentorial, infratentorial, and skull-base lesions report four patients—two male and two female—who experienced TCR episodes intraoperatively (incidence: 2.1%).14 Three additional patients had a TCR episode just at the end of their operation when the skin sutures were being applied, while in the other cases an episode of the TCR occurred when a brain tumor sample was being taken from just below the lateral wall of the cavernous sinus. Anatomical Areas, Step of Procedure It is important to be extra vigilant during certain steps of surgical procedures, especially during the manipulation of certain anatomical areas because handling those areas may provoke intense TCR episodes. Manipulation on or just beneath the lateral wall of the cavernous sinus (near the central course of the trigeminal nerve) has been associated with triggering TCR episodes.42 Accordingly, to prevent the TCR from occurring, surgeons should alert anesthesiologists before starting to work around the area of lateral wall of the cavernous sinus. Similarly, dural handling has been reported to incite TCR episodes and should therefore be carefully monitored. The preparation of nasal mucosae and the sinus ethmoidalis during nasal procedures, including transsphenoidal pituitary surgeries and paranasal sinus operations, has resulted
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TABLE 13.2 Surgeries Commonly Associated with Episodes of the TCR1 Skull-base neurosurgery Transsphenoidal and transnasal pituitary surgeries Cerebellopontine angle surgeries Cavernous sinus surgeries Microvascular decompression for trigeminal neuralgia Balloon compression rhizotomy of the trigeminal ganglion Skin flap elevation in craniotomy Craniofacial surgeries Osteotomies Soft-tissue manipulation in the region innervated by the trigeminal nerve Le Fort I osteotomy Midface fracture reduction Elevation of complex zygomatic fractures Distraction or insufflation of the temporomandibular joint Craniofacial pain surgery Orofacial surgeries Rhinoplasty Maxillofacial surgeries, especially bilateral sagittal split ramus osteotomy Mechanical stimulation of the ocular and periocular structures (strabismus surgery, etc.) Blepharoplasties
in bradycardia that progresses to transient asystole and hypotension, probably because of the direct stimulation of the ethmoidal nerve.43 The parabrachial nucleus and the KöllikerFuse nucleus play a pivotal role in the mediation and maintenance of such autonomic responses induced by the (maxillomandibular) nasotrigeminal reflex, a subtype of the TCR.8,13,44–46 Similarly, stimulation of the sensory branch of the trigeminal nerve in the columellar area in rhinoplasty has been reported to provoke TCR episodes, even under general anesthesia.33 Abrupt and sustained surgical stretching or manipulation, as well as direct stimulation of the trigeminal nerve, can provoke an intense TCR compared with smooth and gentle traction and so should be avoided.24 In cases of ablative procedures for trigeminal neuralgia, insertion of the needle may produce bradycardia and hypotension, but those events may be vasovagal responses rather than a TCR phenomenon. TCR events have been noted during ablative stimuli (chemical, electrical/thermal, mechanical). Among all of the possibilities, the balloon decompression step is most capable of inciting intense TCR episodes that may manifest variably, including bradycardia/asystole, arrhythmias, hypertension, and tachycardia.47 In some medical centers, anticholinergic agents are administered routinely before the actual decompression procedure begins.
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In craniotomies, TCR episodes can be provoked during a number of different steps, including scalp nerve block, skull pin fixation, skin flap elevation, dural opening, tumor handling at or near the vicinity of the trigeminal nerve, dural closure, and even skin closure. Again, anesthesiologists should be extra vigilant during these neurosurgical steps. Type, Frequency and Intensity of the Stimulus Traction, or abrupt stretching, of the nerve is the factor that is most capable of inciting TCR episodes.24 In general, the intensity of an episode is directly proportional to the strength of the stimulus. Therefore, the greater the traction at or near the nerve, the greater will be the chance of a TCR event. This relationship holds for the majority of TCR episodes reported in the literature; however, recent reports by Chowdhury et al. highlighted the fact that even mild traction of the skin may provoke a highly potent TCR event. Therefore, other factors also regulate the intensity of TCR phenomena in certain situations. Similarly, in general, mechanical stimuli, such as stretch, seem to be the most powerful provoking factors; however, chemical, thermal, and electrical stimuli have also been found to incite TCR events.
Physiological Variables If we know the various risk factors for the TCR, we can try and prevent the reflex from occurring by avoiding these factors. Physiological risk factors have been shown to be important in relation to the TCR. In this regard, many studies of the OCR, a subtype of the TCR, have implicated several physiological variables, including hypercapnia, hypoxemia, acidosis, age (more common in children), light anesthesia, and drugs, such as narcotics, propofol, calcium channel blockers, and beta-blockers.48 Although there are no direct studies of risk factors for the TCR, factors affecting the OCR can be considered to affect the TCR as well. Potent, rapidly acting narcotics may augment the vagal tone and can potentiate the reflex by inhibiting the sympathetic nervous system.24,28,48–51 Beta-blockers also potentiate a vagal response by reducing the sympathetic activity of the heart. Calcium channel blockers act by peripheral arterial smooth muscle relaxation, causing vasodilation that leads to hypotension.52 Manipulation of any of the branches of the trigeminal nerve leads to potentiation of these drugs and a worsening of the vagal effect.
OTHER SITUATIONS MIMICKING THE TCR Bradycardia and hypotension episodes similar to those which occur with the TCR can also occur with other reflexes, such as a vasovagal reflex, which can be induced by pain, hypovolemia, and panic.53–55 A loud, horrible sound, a fearful scene, or an unpleasant smell can frighten an awake patient and may provoke a vasovagal reflex during a surgical procedure in the vicinity of the trigeminal nerve.
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ANESTHETIC AGENTS The TCR is one of the autonomic reflexes in human beings and is thought to be phylogenetically similar to the protective diving reflex in birds and amphibians.42 Indeed, the TCR may have a protective role in human beings, but still, the reflex can be catastrophic, and bradycardia can progress to asystole and even, occasionally, death.27,47,56,57 One of the main features of balanced and safe anesthesia is that it should blunt the autonomic reflexes, so, as with any other autonomic reflexes, the TCR is controlled to ensure the safety of patients. Different anesthetic agents can modulate the TCR differently, some dampening the reflex and some amplifying the response. The TCR occurs less commonly with sevoflurane and desflurane compared with halothane, ketamine is associated with a decreased incidence of the reflex compared with propofol, and sevoflurane has a lower incidence than both halothane and propofol, while fast-acting opioids exaggerate the OCR and thus very likely the TCR.58–65 Amplification of the response can have some very serious consequences. It is interesting to know the various mechanisms by which different anesthetic agents modulate the TCR differently, because such knowledge can be helpful in reducing the incidence of the TCR and may increase safety for patients. Anesthetics can alter the TCR at many sites within the brain stem circuitry, including (1) the primary afferent pathway (the sensory nerve endings of the trigeminal nerve via the Gasserian ganglion to the trigeminal nucleus) that synapses upon neurons in the sensory trigeminal nucleus and (2) secondorder neurons to the efferent cholinergic cardioinhibitory neurons in the nucleus ambiguus, by acting on the synaptic neurotransmission at either presynaptic or postsynaptic sites.66 Second-order neurons in the trigeminal nucleus have been identified as glutamatergic by both pharmacological and immunohistochemistry methods.67,68 In a study by Wang et al., the stimulation of trigeminal nerve endings was shown to evoke excitatory postsynaptic currents (EPSCs) that activate postsynaptic N-methyl-daspartate (NMDA) receptors as well as non-NMDA receptors. NMDA receptors were found to be responsible for a slow component (with a long decay phase) and were blocked by the selective NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP-5). Non-NMDA receptor activation was shown to evoke a fast and large EPSC current response that was completely blocked by the selective AMPA/kainate receptor antagonist 6-cyano-7-nitroguinoxaline-2,3-dione. AMPA/kainate and NMDA glutamatergic receptor antagonists together could completely block stimulation-evoked EPSCs.19 In this study, the latency and conduction velocity of the stimulation-evoked EPSCs in either the trigeminal sensory nucleus or efferent parasympathetic cardiac neurons was not changed significantly by the anesthetic drugs (ketamine, propofol, isoflurane, and fentanyl) that were tested. The EPSCs’ peak amplitude and area showed a varied synaptic response to the different drugs.19 Neurotransmission in afferent limbs (via trigeminal sensory neurons in the spinal trigeminal nucleus) and efferent limbs (via polysynaptic pathways to premotor parasympathetic cardiac neurons in the nucleus ambiguus) is mediated by glutamatergic pathways, thereby activating both the NMDA and AMPA/kainate receptors at both sites. The sensory trigeminal nuclei receive inhibitory GABAergic, glycinergic, and excitatory glutamatergic neurotransmission.68–70 The combined anatomical, electrophysiological, and pharmacological analysis carried
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out in studies indicates that spinal trigeminal neurons are coupled to the TCR afferent pathway via direct, monosynaptic excitatory glutamatergic synapses activating both the NMDA and AMPA/kainate receptors in the trigeminal nucleus. At the same time, the neurotransmission in the parasympathetic cardiac neurons in the nucleus ambiguus, which are related to the TCR efferent pathway, is mediated by polysynaptic pathways. Apart from possessing glutamatergic pathways, these neurons also have excitatory serotonergic and muscarinic acetyl cholinergic pathways involved in the modulation of the TCR.71,72 In the Wang et al. study, ketamine probably inhibited both the NMDA and AMPA/kainate receptor-mediated synaptic responses in the afferent and efferent pathways while isoflurane and fentanyl did not have any effect on the afferent pathway, but synaptic transmission of the efferent pathway was inhibited by isoflurane yet was enhanced by fentanyl.19 Either isoflurane and fentanyl act on receptors that are more densely located near the synapses surrounding cholinergic cardiac neurons, or the subunit composition of these receptors are more readily modulated by these agents than are receptors that are involved in the neurotransmission at the afferent pathway.19 Most likely, NMDA receptors are responsible for the inhibition of responses in the cases of ketamine and isoflurane at the efferent pathway. Isoflurane is likely to inhibit the NMDA receptors in the efferent pathway, but not in the afferent pathway, of the trigeminal nucleus. Isoflurane significantly inhibited the amplitude of evoked EPSCs at efferent neurons but not at afferent ones. The disparate responses at the two sites may be related to the different sensitivity, or selectivity, of the receptors involved in glutamatergic neurotransmission at these sites. NMDA receptors are tetramers composed of two NR1 and two NR2 subunits, which bind glycine and glutamate, respectively. Isoflurane is reported to be a competitive antagonist at the NMDA receptor glycine-binding site.73 Isoflurane is also reported to depress inhibitory GABAergic neurotransmission that takes place through endogenous nicotinic receptors to the parasympathetic cardiac neurons.74 Thus, smoking is associated with a greater likelihood of occurrence of the TCR. Many of the anesthetic agents act as NMDA antagonists. Ketamine is a prototype of a noncompetitive NMDA antagonist. It antagonizes NMDA receptors by both open-channel and closed-channel blockade and is in turn associated with a decreased frequency of opening. Ketamine has a high specific selectivity for glutamatergic neurons. Because it decreases the duration of evoked potentials in both afferent and efferent pathways, ketamine anesthesia is associated with a reduced TCR incidence and intensity during surgeries involving trigeminal nerve stimulation. Fentanyl most likely acts via the stimulation of µ-opioid receptors to enhance glutamate release and/or postsynaptic glutamate receptor activation. Anesthetics and narcotics act mainly at the level of sensory receptors within the spinal cord and sometimes at the level of the cerebral cortex.42 Thus, electrical impulses can be transferred through nerve fiber even when the patient has been administered a deep level of general anesthesia.
LOCAL ANESTHETICS Local anesthetics, such as lignocaine, block sodium channels and, thereby, nerve conduction. Unlike general anesthetics, which act on sensory receptors, thus sparing the TRIGEMINOCARDIAC REFLEX
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neurotransmission of electrical impulses through the nerve fiber, local anesthetics block the electrical transmission, ultimately cutting off the reflex arc. As a result, local anesthetics might help abort the TCR in spite of the failure to relieve it by anticholinergics. Some studies report that prophylaxis of TCR can be better achieved with local anesthetic infiltration or nerve block.75–77 Apart from reducing the incidence of the reflex, its severity is also decreased after the block. Misurya et al. reported that both atropine and retrobulbar block by local anesthetic reduced the OCR rate by 10–20%, but when both were used together, the OCR could be completely suppressed.77 Some reports indicate that a peripheral TCR can still be evoked even when a block, such as scalp block, is administered.78 One report advocates the application of a local anesthetic at the root entry zone of the trigeminal nerve, but local anesthetics can themselves precipitate bradycardia and hypotension (as, e.g., in the preparation of a columellar area in rhinoplasty).33
ANTICHOLINERGICS Anticholinergic prophylaxis has been reported to decrease the incidence of OCRs.79–81 However, atropine may cause bigeminy and increase ectopic beats, and these arrhythmias are more persistent than the OCR.82 Moreover, recent studies report that atropine is not universally as effective as OCR prophylaxis, and it is even said to be ineffective in the usual intramuscular premedication doses.83,84
NARCOTICS Fast-acting opioids (fentanyl, sufentanil, and remifentanil) have been reported to show an exaggerated response of the OCR. Arnold et al. reported that rapidly acting opioids enhance OCRs that are elicited by extraocular muscle tension during strabismus surgery.63 Remifentanil can cause bradycardia either by parasympathetic activation or by direct negative chronotropic effects.85 In one study, a group that received ketamine and remifentanil had more OCR incidences than a group that was administered ketamine and sevoflurane, and similarly, a group that was given midazolam and remifentanil had more OCR episodes than a group that received midazolam and sevoflurane.64 Morphine has been reported to inhibit the TCR, provided that the spinal cord is intact—a finding suggesting that at least part of the action of systemic morphine is due to activation of descending inhibition.
INHALATIONAL ANESTHETIC AGENTS The major influence on the incidence of the TCR may be due to the vagolytic effect of inhalational agents: the less the vagal activity, the less is the incidence of the TCR. Cardiac vagal activity, measured by variability of the heart rate, has been reported to be least with desflurane and sevoflurane, intermediate with isoflurane and enflurane, and greatest with halothane.86 TRIGEMINOCARDIAC REFLEX
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OCR incidence has been found to be no different between desflurane and sevoflurane anesthesia.59 Thus, both agents can be safely used.
KETAMINE Ketamine has been associated with a decreased incidence of the OCR compared with propofol. Both a single bolus and continuous infusion of ketamine have been reported to reduce OCR incidence.61,62 Ketamine’s action may be due to sympathomimetic effects and inhibition of the parasympathetic reflex, whereas propofol increases bradycardia through a central sympatholytic effect and vagal stimulation.87,88 Hahnenkamp et al. reported that the incidence of the OCR was lowest with the continuous infusion of ketamine, compared with sevoflurane, halothane, and propofol, in that order.59,61
OTHER DRUGS Onyx (dimethylsulfoxide) is a liquid embolic system used for presurgical embolization in neurosurgery. Injection of this material into vessels in close proximity to the trigeminal nerve or its branches has been reported to evoke a vagal response from the TCR.89 To avoid catastrophic complications, authors have advised either pretreatment with anticholinergic drugs or the prophylactic placement of a transvenous pacemaker.
CANNABINOIDS Cannabinoid agonists (HU 210) have been reported to inhibit trigeminal withdrawal reflexes.90 Trigeminal and spinal reflexes are sensitive to these agonists if the spinal cord is intact. Part of their action appears to be due to the activation of descending inhibition.
TONABERSAT Tonabersat (SB-220453), a novel benzopyran with anticonvulsant properties, has been shown to attenuate trigeminal nerve–induced neurovascular reflexes.91 Tonabersat, carabersat, and other anticonvulsants could block trigeminal parasympathetic reflexes; therefore, these agents may have a therapeutic benefit under conditions that are likely to incite those reflexes.
ANESTHETIC DEPTH Anesthetic depth has been reported to affect the incidence of the TCR. A bispectral index (BIS) of 40–50 in pediatric patients under general anesthesia led to a significant decrease in the incidence of the OCR.30 In deeply anesthetized animals, an algesic stimulus is unable to determine whether there are any cardiorespiratory effects as a result of various reflexes. TRIGEMINOCARDIAC REFLEX
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ANESTHETIC MANAGEMENT OF THE TCR Manipulation of the trigeminal nerve and its branches may cause an episode of the TCR even if anticholinergic drugs are used.92 The cessation of stretching, manipulation, and/or stimulation forms the most important part of treatment. The most important intervention for managing the TCR is to pay proper attention to its potential danger and minimize any mechanical stimulation of the nerve. Identifying and, if possible, modifying risk factors, as well as administering prophylactic treatment with either vagolytic agents or peripheral nerve blocks in case of peripheral manipulation of the trigeminal nerve, should be undertaken. Meticulous, vigilant monitoring intraoperatively under anesthesia is a must. In case the reflex still occurs, manipulation of the nerve should cease and vagolytic agents should be administered. Continuous, and especially repeated, episodes of the TCR necessitate the administration of a high dose of an anticholinergic, preferably atropine. If the episode is still not resolved, even adrenaline may be prescribed.48
POSTOPERATIVE FUNCTIONAL CONSEQUENCES OF INTRAOPERATIVE OCCURRENCES OF THE TCR The occurrence of the TCR in the intraoperative period has been associated with a poor outcome. Patients operated on for vestibular schwannomas have had their hearing affected by the occurrence of the TCR intraoperatively.6,40 Gharabaghi et al. reported that hearing was preserved in just 11.1% of patients in a group that had experienced the TCR intraoperatively, compared with a much better 51.4% in a group that had not experienced the reflex; overall, hearing was preserved in 47% of the patients.40 Schaller et al. compared the occurrence and incidence of tinnitus in patients who did and did not have an intraoperative TCR episode.6 Seventeen percent of patients in the non-TCR group had ipsilateral tinnitus postoperatively, compared with up to 60% of the patients in the TCR group. The mechanisms behind increased hearing loss and tinnitus after the TCR are not clear, but it is assumed that intraoperative hypotension initiated by the reflex might be the principal cause. One of the things learned from the anesthetist’s side of these important observations is that it is no longer only the (neuro)surgeon`s skills that substantially influence the postoperative functional outcome, but also the intraoperative changes in vital parameters that are supervised by the (neuro) anesthetists. Such observations further underline the importance of the TCR away from being viewed as a simple intraoperative phenomenon to one of, if not the, principal intraoperative complications that have to be avoided. In such a context, further future research is needed.
FUTURE RESEARCH Anesthesia-related factors have been found to influence TCR events;93,94 however, randomized controlled trials should be conducted to explore this tentative hypothesis. Anesthetic depth–related influences on TCR episodes also need to be addressed in future studies. Differential features of vasovagal and TCR episodes need to be investigated, including whether there is any overlap between the pathways that play a role in inciting either kind of episode. Preventing TCR episodes is another area that requires further attention. TRIGEMINOCARDIAC REFLEX
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The last few years have seen a better understanding of the role and importance of the TCR, and that understanding has influenced anesthesiological research in such a way that a knowledge of the vital parameters involved has once again become important.
CONCLUSION Anesthesiologists have a very important role in the prevention, recognition, and treatment of the TCR, whose occurrence is associated with poor and, sometimes, life-threatening outcomes. The various risk factors (patient related, technique related, procedure related, and drug related) need to be assessed, and proper prophylactic measures undertaken, to avoid occurrences of the TCR. Sustained, abrupt traction of the trigeminal nerve must be avoided, and gentle manipulation, if at all required, applied to prevent episodes of the TCR. Various anesthetic and analgesic drugs, at clinically relevant concentrations, regulate the receptors at each site within the TCR reflex arc, and, if possible, anesthetic technique can be modified to prevent the TCR from occurring. Monitoring the depth of anesthesia (via, e.g., the BIS and the cerebral state index) and maintaining an adequate depth are advised.
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