The TCR is a critical cardiovascular event found in several surgical procedures involving a structure innervated by the trigeminal nerve. TCR occurs during treatment of endovascular embolization, which results in an intense autonomic disturbance of the heart that manifests as the sudden onset of bradycardia, hypotension, arrhythmias and even heart arrest. Sudden hemodynamic fluctuations may affect the course of surgery and patient prognosis. Therefore, TCR and related risk factors have gained much interest during recent years. In this study, we have analyzed, the relation between DAVF and TCR occurrence highlight a strong association. We also found a higher pooled risk for embolization vessel supplied by the middle meningeal artery for hypotension and occurrence of asystole during TCR, suggesting a more severe reflex variant under these conditions.
The physiological mechanism of TCR is that signals triggered by either peripheral or central stimulation on the sensory nerve endings of the trigeminal nerve are relayed to the sensory nucleus of the trigeminal nerve. This afferent pathway continues along the short internuncial nerve fibers in the reticular formation to connect with the efferent pathway in the motor nucleus of vagus nerve and nucleus ambiguus. The fibers of vagus or sympathetic nerves end in the myocardium, leading to autonomic changes that usually manifests as a negative chronotropy . However, there are two major subtypes of peripheral or central TCR. Previous studies have suggested that peripheral stimulation of the trigeminal nerve co-actives vagal and sympathetic nerves, resulting in both hypertension (peripheral vasoconstriction) and bradycardia . By contrast, central stimulation may cause hypotension and bradycardia by generating profound activation of the cardiac vagal branch and specific inhibition of the inferior cardiac sympathetic nerve .
In this study, we observed that all the TCR patients presented with heart rate deceleration > 20%, or even cardiac arrest, but just 13 patients experienced blood pressure reduction. On the contrary, 14 patients presented with blood pressure increase. Therefore, we suggest that central stimulant from chemical agents and distinct endovascular embolization might share the common efferent pathway for vagus activation, but the induce of inhibitory or promotive effect on efferent sympathetic pathway may co-existence in the process of central TCR, which depends on the site of stimulation. Hypertension may be associated with a greater susceptibility of sympathetic nerve stimulation, while the occurrence of hypotension is partly in a heart-rate-dependent manner, with significant blood pressure reduction when the heart rate is too slow. The low incidence of hypotension in this study may be related to our team's close monitoring of intraoperative hemodynamic changes, which usually prevented the continued deterioration of TCR.
In this cohort, we found that in the TCR group, the patients with protopathy of DAVF accounted for 77.8%, and the patients whose supplying vessel was the middle meningeal artery accounted for 70.4%, which was significantly higher than that in the control group. Therefore, we suspected that the patients with DAVF or middle meningeal artery embolization are the risk factors for TCR episode during DMSO or Onyx injection. These results are consistent with the previous case reports that TCR occurs mainly in patients with DAVF during cerebrovascular interventional embolization operation.
DAVFs are abnormal connections between dural arteries and venous sinuses. The dura mater is innervated in part by branches of the trigeminal nerve and receives vascular supply from the meningeal artery as well as meningeal branches of the occipital artery . These vessels are primarily involved in the blood supply to the sensory area of the trigeminal nerve. Therefore, when the meningeal artery receives mechanical or chemical stimulation, trigeminal nerve excitability increases, leading to the episode of TCR. To some extent, these results support the anatomically specific triggering of TCR. Anesthesiologists and neurosurgeons should be alert to the occurrence of TCR during DAVF embolization.
Studies have confirmed that Onyx has no effect on hemodynamics by itself . However, mechanical stimulation of the trigeminal nerve during DMSO or Onyx injection is an essential inducement of TCR, and this effect is closely related to the dose and rate of injection . Experts recommend that the injection rate of both DMSO and Onyx should not exceed 0.1 ml/min . In this study, all procedures were performed by the same experienced neurosurgeon. Therefore, it seems that we can ignore the effect of injection speed on this study.
The occurrence of TCR is challenging to predict, and there is no precise detection index. Currently, preventive measures for TCR mainly include the use of anticholinergic drugs to reduce vagal excitability and increase the heart rate . However, experts considered that preemptive administration of anticholinergics for the prevention of TCR may be ineffective. It has been observed that bradycardia and hypotension in TCR includes both excessive activation of vagal and inhibition of adrenergic vaso-constriction after electrical stimulation of the spinal trigeminal tract and trigeminal nuclear complex . Atropine can only block the cholinergic fibers, yet cannot completely prevent bradycardia or hypotension. In this study, we also found that some patients often showed MAP increasing during embolization treatment, and atropine may increase the risk of hypertension while increasing the heart rate. In addition, atropine is at risk of refractory arrhythmia, so prophylactic use is not recommended . The results of this study showed that although there was no significant difference in HR between the TCR group and control group, preoperatively and before embolization, however, multivariate logistic regression analysis showed that bradycardia before embolization was a risk factor for TCR. Therefore, it may be necessary to prophylactically correct bradycardia before embolization in high-risk patients.
In view of the large number of similar TCR events, the recognition and treatment of TCR has become increasingly adequate. The surgeon should first be informed to discontinue the procedure once TCR has occurred, resulting in a deterioration in hemodynamics. Withdrawal of stimulation usually reverses this phenomenon immediately, without the need for anticholinergic drugs. For refractory bradycardia and hypotension, anticholinergic agents such as epinephrine or atropine should be initiated. Furthermore, we need to reassess and increase the depth of anesthesia. A meta-analysis  showed that lighter anesthesia (CSI > 60) were associated with a 1.2-fold increased incidence of bradycardia and a 4.5-fold increased risk of cardiac arrest than deeper anesthesia (CSI < 40). In this study, all patients had moderate anesthesia depth, and there was no significant difference in BIS value between the two groups. During operation 4 patients occurred cardiac arrest which resumed spontaneous circulation after discontinuation of the procedure and administration of atropine or a small dose of epinephrine. In addition, 6 patients with recurrent HR < 40 bpm were given atropine 0.5mg, and the TCR was successfully corrected. However, the incidence of postoperative adverse events were similar between the two groups, which may be mainly attributed to the in-depth understanding of TCR and timely treatment.
The limitation of this study is being a single-centered study with a relatively limited sample size and potential bias in patient selection. Meanwhile, this study is a retrospective study, in which only BIS values were used as the evaluation index for anesthesia depth. It is difficult to track the real-time blood concentration of various anesthetics, and it is impossible to exclude the influence of drugs on TCR episode.
In summary, the TCR episode may due to chemical stimulus of DMSO and Onyx injection, leading to a significant decrease in HR under a standardized anesthetic protocol. This study confirms that patients with DAVF, CCF and middle meningeal artery embolism are the risk factors for TCR during Onyx endovascular embolization. Therefore, anesthesiologists and neurosurgeons should strengthen the identification of TCR risk factors, and strive to achieve early prevention and treatment to reduce the incidence of TCR-related adverse events.