**6. Clinical significance of the trigeminocardiac reflex and why it should be treated**

Most authors recognized that the TCR is a transient, but potentially life-threatening response to any manipulation of the fifth cranial nerve subsiding with latency after cessation of the stimulus. But, in case of the development of severe bradycardia and asystole, the administra‐ tion of peripheral muscarinic acetylcholine receptor blockage at the heart is warranted in addition to cessation of the stimulus. Even so often mentioned, but still not understood from all: The vagal blockage potential of atropine is only insufficient for the prevention of hypo‐ tension or bradycardia.

Rath et al. reported a case of asystole occurring in a patient who was undergoing percutaneous retrogasserian glycerol rhizolysis for trigeminal neuralgia [72]. Immediately after the injection of anhydrous glycerol, the patient became unresponsive; the pulse became impalpable, blood pressure unrecordable, the ECG showed asystole and had a respiratory arrest. The patient regained consciousness and heart rate and blood pressure returned to normal after 30 seconds with oxygen and IV atropine [72]. Prabhakar et al. also reported a case of sudden asystole without prior bradycardia which occurred during surgery for cerebellopontine angle tumour [72]. This case was just managed by cessation of the manipulation without the administration of vagolytic agents [74]. Fayol et al. also reported a five-year-old boy who was operated for strabismus and possibly died due to OCR which developed on underlying myocarditis [74]. These cases demonstrate the (clinical) importance of the TCR which may range from mild bradycardia which responds to simple cessation of the stimulus to asystole and severe bradycardia requiring additional intervention with vagolytics. In some rare but serious cases, it may lead to death if not detected early and appropriate measures taken.

In addition, hypotension which occurs during the TCR may lead to myocardial and cerebral hypoperfusion/infarction in those who are at risk for these conditions. It has also been shown that the hypotension may lead to worse functional outcomes in hearing/vestibular function in patients operated for vestibular schwannoma compared to those who do not develop the reflex [25, 75]. In a prospective study of 100 patients after vestibular schwannoma surgery, Ghara‐ baghi et al. found out that the occurrence of TCR was 11% [25]. With an overall hearing preservation of 47%, 11.1% of the patients in the TCR group and 51.4% of those in the non-TCR group experienced preserved hearing function postoperatively [25]. In addition, in cases involving larger tumours, an intraoperative TCR was associated with a significantly worse postoperative hearing function during vestibular schwannoma surgery suggesting that the hypotension following TCR is – in addition to the tumor size – a negative prognostic factor for hearing preservation in patients undergoing VS surgery [25]. In another study, Schaller et al. compared the occurrence and persistence of tinnitus in patients with and without TCR [76]. Among 36 patients operated for vestibular schwannoma, TCR occurred in 17% and influenced the occurrence of postoperative ipsilateral tinnitus: The overall incidence of postoperative ipsilateral tinnitus was 22%. A total of 60% patients in the TCR subgroup and only 17% of in the non-TCR subgroup experienced ipsilateral tinnitus postoperatively [76]. These studies show that there is a tendency for increased complication rates in patients who developed TCR compared to those without it, again stressing the importance of looking it carefully during neurosurgical and especially skull base surgical procedures.

### **7. Management of the trigeminocardiac reflex**

The best and more effective treatment for TCR is still a matter of intensive debate [77–86]. It is beyond the scope of this manuscript to discuss all this in detail. Without any doubt, the application of atropine is not the only modality of treatment, based on cellular knowledge of the reflex and also based on the meanwhile extensive clinical experience. To the authors opinion, the first and the most important "management option" for the TCR is to be aware of its potential danger and to minimize any mechanical/thermal stimulation of the nerve during any interventional procedure in or around the skull base.

According to the empirical experience on the TCR, and according to the current level of evidence [87], we have summarized the current recommendation as follows [35]:

Risk factor identification and modification (*Evidence Grade D*)

Prophylactic treatment with either vagolytic agents or peripheral nerve blocks in case of peripheral manipulations of the trigeminal nerve (*Evidence Grade B–C*)

Careful cardiovascular monitoring during anaesthesia especially in those with risk factors for TCR (*Evidence Grade B–C*)

Treatment of the condition when it occurs (*Evidence Grade B–C*)

**•** cessation of the manipulation

addition to cessation of the stimulus. Even so often mentioned, but still not understood from all: The vagal blockage potential of atropine is only insufficient for the prevention of hypo‐

Rath et al. reported a case of asystole occurring in a patient who was undergoing percutaneous retrogasserian glycerol rhizolysis for trigeminal neuralgia [72]. Immediately after the injection of anhydrous glycerol, the patient became unresponsive; the pulse became impalpable, blood pressure unrecordable, the ECG showed asystole and had a respiratory arrest. The patient regained consciousness and heart rate and blood pressure returned to normal after 30 seconds with oxygen and IV atropine [72]. Prabhakar et al. also reported a case of sudden asystole without prior bradycardia which occurred during surgery for cerebellopontine angle tumour [72]. This case was just managed by cessation of the manipulation without the administration of vagolytic agents [74]. Fayol et al. also reported a five-year-old boy who was operated for strabismus and possibly died due to OCR which developed on underlying myocarditis [74]. These cases demonstrate the (clinical) importance of the TCR which may range from mild bradycardia which responds to simple cessation of the stimulus to asystole and severe bradycardia requiring additional intervention with vagolytics. In some rare but serious cases,

In addition, hypotension which occurs during the TCR may lead to myocardial and cerebral hypoperfusion/infarction in those who are at risk for these conditions. It has also been shown that the hypotension may lead to worse functional outcomes in hearing/vestibular function in patients operated for vestibular schwannoma compared to those who do not develop the reflex [25, 75]. In a prospective study of 100 patients after vestibular schwannoma surgery, Ghara‐ baghi et al. found out that the occurrence of TCR was 11% [25]. With an overall hearing preservation of 47%, 11.1% of the patients in the TCR group and 51.4% of those in the non-TCR group experienced preserved hearing function postoperatively [25]. In addition, in cases involving larger tumours, an intraoperative TCR was associated with a significantly worse postoperative hearing function during vestibular schwannoma surgery suggesting that the hypotension following TCR is – in addition to the tumor size – a negative prognostic factor for hearing preservation in patients undergoing VS surgery [25]. In another study, Schaller et al. compared the occurrence and persistence of tinnitus in patients with and without TCR [76]. Among 36 patients operated for vestibular schwannoma, TCR occurred in 17% and influenced the occurrence of postoperative ipsilateral tinnitus: The overall incidence of postoperative ipsilateral tinnitus was 22%. A total of 60% patients in the TCR subgroup and only 17% of in the non-TCR subgroup experienced ipsilateral tinnitus postoperatively [76]. These studies show that there is a tendency for increased complication rates in patients who developed TCR compared to those without it, again stressing the importance of looking it carefully during

The best and more effective treatment for TCR is still a matter of intensive debate [77–86]. It is beyond the scope of this manuscript to discuss all this in detail. Without any doubt, the application of atropine is not the only modality of treatment, based on cellular knowledge of

it may lead to death if not detected early and appropriate measures taken.

neurosurgical and especially skull base surgical procedures.

**7. Management of the trigeminocardiac reflex**

tension or bradycardia.

100 Abnormal Heart Rhythms


We can see that there is a lack of good evidence in the TCR, mostly based on the literature that is predominantly based on case reports and only seldom case-control studies. Additionally, this modest evidence is underlined by a substantial publication bias. As a consequence of this, the recommendations are more general as one might wish.

The risk of TCR, however, should be considered in any interventional procedure, especially at the skull base that takes place in trigeminally innervated structures. We have developed recently a thinking model that would give a preoperative idea about the risk of the TCR that can be expected in surgery in a specific neuroanatomical region [36]. If any mechanical stimulation to the trigeminal nerve is necessary, which is a rather "robust" nerve, it should be as gentle as possible. We have now different preoperative thinking models [36, 37] that should help the surgeon as well the anaesthetics to delimit the intraoperative occurrence of the TCR before operation and to perform adapted precautions. These manoeuvres should help to further decrease the incidence of the TCR.

If working in the vicinity of the trigeminal nerve or its branches, there should be an intensive communication between surgeon and anaesthesist. From our experience, this is perhaps one of the key factors of success. Continuous intraoperative haemodynamic monitoring has been shown to be an appropriate medium to interrupt any interventional manoeuvres immediately upon the first signs of occurrence of TCR. This technique has been proven to be sufficient to return to normal haemodynamic levels without the necessity of additional (anticholinergic) medication, if the cessation of stimulus was within a considerable time span before postoper‐ ative persistent neurological deficits occur [77, 78]. Following this empiric strategy, an uneventful further intraoperative and postoperative course may be achieved.

If controlled arterial hypotension is already preoperatively planned to be performed during the interventional procedure, the prophylaxis of TCR is better accomplished with local anesthetic infiltration or block of the nerve(s) which convey afferent stimuli leading to the reflex. Shende et al. studied the efficacy of peribulbar block with bupivacaine in patients operated for retinal detachment [79]. They collected 60 patients who were randomly assigned to receive either bupivacaine or IV morphine and studied the incidence and severity of the OCR. Apart from significantly reducing the incidence of OCR (30% vs 70%), peribulbar bupivacaine also attenuated the severity of the reflex [79]. Gupta et al. studied the effect of peribulbar block in comparison to topical application of local anesthetic in children scheduled for strabismus surgery. They found out that the incidence and severity of OCR intraoperatively was significantly reduced in children who received a peribulbar block [80]. Misurya et al. studied the effectiveness of prophylactic intravenous atropine sulphate which blocks the peripheral muscarinic receptors at the heart and retrobulbar xylocaine hydrochloride, which blocks the conduction at ciliary ganglion on the afferent limb of OCR. In this study, both atropine and retrobulbar xylocaine reduced the rate of OCR to 10–20%. But, when both methods were used together, they were able to completely suppress the OCR [81].

If there is no contraindication to intravenous anticholinergics, atropine and/or glycopyrrolate IV may be used to partially prevent a TCR [82]. Hunsley et al. evaluated the efficacy of IV atropine and glycopyrrolate in the prevention of the OCR in children operated for strabismus. They tested different doses of the two drugs, glycopyrrolate 5 and 7.5 mg/kg and atropine 10 and 15 mg/kg. Overall, there is a reduction in the rate of bradycardia by 23.8–33.3% [83]. But these authors noticed that even higher doses of the two drugs, atropine 15mg/kg and glyco‐ pyrrolate 7.5mg/kg i.v., given 5 min before induction of anesthesia, are not sufficient to protect completely against the OCR in children. In a study done to evaluate the efficacy of IV or IM vagolytic agents (atropine and glycopyrrpolate) in children undergoing squint surgery, Mirakhur et al. evaluated them in a controlled study and found out that the administration of the anticholinergic agents in both the IV and the IM forms may decrease the occurrence of the OCR [84]. The overall frequency was approximately 40% (62 of 160 patients), but was 90% in those patients who did not receive anticholinergic drugs [84]. The authors concluded that the administration of anticholinergic drugs, even by the IM route, decreased the frequency, and glycopyrrolate 10 mg per kg being the most efficacious by this route [84]. As consequences of this literature and our own experience, the administration of anticholinergics has shown to be ineffective in completely preventing the TCR [73, 88]. The use of atropine is, nowadays, therefore questioned because cholinergic blockage reduces but does not totally prevent either bradycardia or hypotension in animals [85]. Another reason is that a trigeminal depressor response includes both the activation of vagal cardioinhibitory fibres and the inhibition of adrenergic vasoconstriction as demonstrated after electrical stimulation of the spinal trigemi‐ nal tract and trigeminal nuclear complex. In addition, atropine may cause serious cardiac arrhythmias itself, especially when halothane is the primary anaesthetic agent and hence the dose must be carefully chosen [86]. Prabhakar et al., for example, reported a 48-year-old female who developed severe bradycardia and hypotension during craniotomy for parietal convexity meningioma; she was unresponsive to atropine and successfully managed with epinephrine [89]. The action of adrenaline is to increase peripheral resistance via alpha-1 adrenoceptor vasoconstriction, so that blood is shunted to the body core, and the alpha-1 adrenoceptor response which is to increase cardiac rate and output [89]. This important case report under‐ scores the fact that TCR may be refractory to atropine and other vagolyticse and may rather need to be managed with epinephrine [89]. One the other hand, the personal experience with atropine is, besides its potential danger as described already earlier, that if given prophylactic in cases of risk for the occurrence of TCR it leads to a smaller change in TCR haemodynamic. In this context, the recently developed different thinking models help to better plan already preoperatively the procedure. This discussion about smaller haemodynamic changes has gained more and more importance during the last years, because of the functional outcome that is influenced by the TCR.

From our experience, the treatment of TCR deserves more attention in the daily practice. If a TCR is elicited, the underlying stimulus has to be stopped until the haemodynamic distur‐ bances have been recovered to normal values. Any occurrence of the TCR corresponds to the intensity of the mechanical/thermal stimulation on the sensory part of the fifth nerve. From own and other clinical experience, abrupt and sustained traction is more likely to evoke the TCR than smooth and gentle manipulations [32–34, 78].
