Abstract
Background
A significant abrupt drop in heart rate is the most frequent complication during percutaneous microballoon compression of the trigeminal ganglion. It is suggested that co-activation of the sympathetic and parasympathetic nervous systems plays an important role in this occurrence. We hypothesized that not only atropine, but also labetalol might be effective in preventing this cardiovascular reflex during percutaneous microballoon compression of the trigeminal ganglion.
Methods
Patients who underwent percutaneous microballoon compression for trigeminal neuralgia between September 2007 and December 2009 were prospectively evaluated. The relationship between the hemodynamic changes and intraoperative use of atropine (0.01 mg/kg) or labetalol (0.05 mg/kg) was compared. One-way analysis of variance with Bartlett's and Tukey's post-tests was used, and a value of p < 0.05 was considered statistically significant.
Results
In total, 119 patients who received percutaneous microballoon compression for trigeminal neuralgia were studied, of whom 38 received atropine before ganglion compression, 36 received labetalol, and 45 received normal saline as a control. Of the patients who received normal saline, 31.3% had moderate bradycardia (heart rate < 50 beats/min), 13.3% had severe bradycardia (heart rate < 40 beats/min), and 7% had arrhythmia. Of the patients who received atropine, 7.8% had moderate bradycardia, 7.8% had arrhythmia, and 5.3% had postcompression tachycardia by the end of ganglion compression. Of the patients who received labetalol, 16.7% had moderate bradycardia, 5.6% had severe bradycardia, and 2.8% had arrhythmia. Systemic blood pressure was markedly elevated straight after compression in all groups and tended to normalize 3 minutes afterwards.
Conclusion
Both atropine and labetalol were able to lower the frequency of bradycardia. Neither of them could abolish episodes of bradycardia during the procedure. Patients receiving labetalol before microballoon compression were subject to a smaller change in hemodynamics. Our findings verified that the sympathetic and parasympathetic nervous systems may be involved in the complex interneuronal interaction of the trigeminocardiac reflex.
Keywords
atropine; labetalol; reflex, trigeminocardiac; trigeminal ganglion: compression; trigeminal neuralgia;
1. Introduction
Percutaneous microballoon compression of the trigeminal ganglion was introduced by Mullan and Lichtor in 1983.1 It is a relatively simple and painless procedure and has been reported to have technical success in 63–97% of cases.2, 3 It has been suggested as a treatment of choice for trigeminal neuralgia.3
Intriguingly, some drastic hemodynamic changes have been observed during this procedure. The most salient one is sudden severe bradycardia, which is usually observed during the initial phase of ganglion compression1, 4 and is termed the trigeminocardiac reflex (TCR). Although the severe bradycardia triggered by the TCR subsides automatically within minutes in most cases, in some instances it ends in cardiac arrest and fatality.5 Thus, continuous intraoperative hemodynamic monitoring is recommended, and administration of atropine and the application of a pacemaker have been suggested as remedies for the abrupt severe bradycardia.6
Interestingly, it has also been suggested that both the sympathetic and parasympathetic nervous systems are involved in the TCR,7, 8 and their complex interplay makes the optimized method to prevent severe bradycardia during compression open to debate. For example, some of our patients receiving labetalol before ganglion compression also experienced less severe bradycardia. Therefore, we set out to prospectively compare the hemodynamic effects in patients receiving atropine or labetalol on severe bradycardia.
2. Methods
The study (IRB 98-3302B) was approved by the Ethical Committee of Lin-Kao Chang Gung Memorial Hospital, Taoyuan, Taiwan. One hundred and nineteen patients who were diagnosed with trigeminal neuralgia and underwent percutaneous microballoon compression of the trigeminal ganglion between September 2007 and December 2009 were identified for the study.
The patient characteristics of the 119 patients included in our study are summarized in Table 1; 38 received atropine and 36 received labetalol 3 minutes before ganglion compression. Forty-five patients received normal saline as a control. Because of the drastic hemodynamic changes during percutaneous microballoon compression of the trigeminal ganglion, a uniform protocol of anesthesia had been established for these patients (Fig. 1). In brief, general anesthesia was induced with propofol (2 mg/kg), fentanyl (3 μg/kg), and cisatracurium (0.2 mg/kg), and was maintained with sevoflurane in oxygen.
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While the neurosurgeon successfully placed the needle into the foramen ovale under fluoroscopy immediately before the balloon compression procedure, both the neurosurgeon and anesthesiologist worked cooperatively and followed exactly the procedures described below. Patients were first administered either normal saline (1 mL), intravenous atropine (0.01 mg/kg), or labetalol (0.05 mg/kg) at random, followed by ganglion compression 3 minutes later. The compression procedure lasted on average 3 minutes.
Hemodynamic parameters such as blood pressure (systolic and diastolic), heart rate, and electrocardiogram tracing were continuously recorded throughout the procedure. The data obtained before balloon inflation, during compression, and immediately after deflation were denoted as Pre (baseline), Post1 and Post2. All the heart rate and blood pressure data were analyzed by commercial statistical software (Prism 5; GraphPad, Sandiego, CA, USA). One-way analysis of variance (ANOVA) coupled with Bartlett's post-test for equal variances and Tukey's multiple comparison post-test for paired columns comparison were deployed for the complex statistics. A value of p < 0.05 was considered statistically significant.
3. Results
3.1. Balloon compression of trigeminal ganglion induced severe bradycardia and arrhythmia without medical treatment
Sixty percent of the 45 patients who did not receive specific pretreatment (the normal saline group) before compression showed a hemodynamic abnormality during the procedure (Table 2). The ganglion compression resulted in moderate bradycardia in 14 patients (31.1%; heart rate < 50 beats/min), and severe bradycardia (heart rate < 40 beats/min) in six (13.3%; Table 1, Fig. 2). Notably, seven patients (15.5%) developed either atrioventricular block, atrial premature contracture, or ventricular premature contracture.
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3.2. Few patients pretreated with atropine (0.01 mg/kg) suffered TCR-induced bradycardia
As shown in Table 2, a total of 38 patients were pretreated with atropine (0.01 mg/kg) before balloon compression of the trigeminal ganglion. Our data demonstrated that patients receiving atropine showed a lower frequency of hemodynamic instability (8 of 38 patients, 21.1%), most of which was moderate bradycardia (3 of 38 patients, 7.8%) or arrhythmia (3 of 38 patients, 7.8%). None of the patients developed severe bradycardia. However, postcompression tachycardia was observed in two patients (5.3%).
When the variability in heart rate was analyzed further, neither the control nor the atropine group showed a baseline difference (mean ± SD: 68.8 ± 13.2 vs. 62.58 ± 12.3 beats/min; Fig. 3A), but a significant difference was observed immediately after compression in the atropine group (55.5 ± 8.9 vs. 70.6 ± 14.2 beats/min, one-way ANOVA, p < 0.05, mean difference −15.09, q = 8.44, 95% CI −23.05 to −7.12; Fig. 3B). This significant heart rate alteration was then masked by the later postcompression tachycardia, but this was not the case for the labetalol group (79.9 ± 12.3 vs. 73.4 ± 13.9 beats/min; Fig. 3C).
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3.3. Patients pretreated with labetalol (0.05 mg/kg) showed a lower frequency of TCR-induced bradycardia
Of the 36 patients who received labetalol (0.05 mg/kg), nine were observed to have either bradycardia or arrhythmia. Of these 36 patients, 16.7% had moderate bradycardia, 5.6% had severe bradycardia, and 2.8% had arrhythmia (Table 2), indicating that labetalol could significantly lower the frequency of TCR-induced bradycardia. However, the quality of the hemodynamic changes in the two groups seemed different. The atropine group did not develop severe bradycardia but were observed to have postcompression tachycardia; conversely, the labetalol group had no postcompression tachycardia but the bradycardia remained.
On further analysis of the heart rate variability, in spite of similar baseline values in the control and labetalol groups (68.8 ± 13.2 vs. 67.5 ± 13.9 beats/min; Fig. 3A), a significant difference was observed immediately after compression (55.5 ± 8.9 vs. 62.8 ± 10.2 beats/min, one-way ANOVA, p < 0.05, mean difference −7.33, q = 4.05, 95% CI −15.39 to 0.73; Fig. 3B). This significant heart rate alteration lasted for 3 minutes after compression (79.9 ± 12.3 vs. 70.1 ± 13.9 beats/min, one-way ANOVA, p < 0.05, mean difference 9.75, q = 5.39, 95% CI 1.69–17.81; Fig. 3C).
3.4. TCR increased both systolic and diastolic blood pressure, an effect that was attenuated by labetalol but not atropine
We further analyzed the effects of labetalol and atropine on TCR blood pressure responses (Fig. 4). As shown in Fig. 4A, both the systolic and diastolic blood pressures were elevated upon compression of the trigeminal ganglion for those in the normal saline group (there having been no difference in the baseline blood pressure for each group; data not shown). In comparison, patients receiving labetalol had relatively stable systolic and diastolic blood pressures compared with those pretreated with either normal saline or atropine immediately after compression (control 158.4 ± 20.6/91.6 ± 11.5, atropine 147.7 ± 37.4/84.4 ± 17.3, labetalol 134.0 ± 25.9/76.6 ± 14.9 mmHg, one-way ANOVA, p < 0.05, mean difference −24.44, q = 7.03, 95% CI 6.95–41.92; Fig. 4B and 4C). This relative hemodynamic stability could be maintained continuously for 3 minutes after compression (control group 136.4 ± 18.1/79.6.6 ± 10.5, atropine group 129.2 ± 25.7/72.5 ±15.4, labetalol group 118.0 ± 24.2/69.8 ± 13.6 mmHg, one-way ANOVA, p < 0.05, mean difference −18.41, q = 5.29, 95% CI 0.93–35.89; Fig. 4B and 4C).
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4. Discussion
The TCR is defined as sudden-onset dysrhythmia, hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve.9 The TCR is known to occur during craniofacial surgery, manipulation of the trigeminal nerve/ganglion, and surgery for lesions in the cerebellopontine angle, cavernous sinus, and pituitary fossa.10, 11, 12
In the present study, transient severe bradycardia (below 40 beats/min) and a simultaneous rise in systemic blood pressure were observed immediately after percutaneous microballoon compression of the trigeminal ganglion. Subsequent rebound tachycardia was then observed at the end of ganglion compression, while at the same time the systemic blood pressure gradually returned to the normal range.
Interestingly, patients who received either atropine or labetalol 3 minutes before ganglion compression showed a lower frequency of severe bradycardia during balloon compression. However, the discrepancy in the hemodynamic effects between the atropine and labetalol groups could not be ignored. For example, the mean heart rate in the atropine group was increased above baseline after compression; however, the two patients with an episode of postcompression tachycardia during and at the end of ganglion compression were in the atropine group. Although the preventive effect was statistically better in the atropine group than in the labetalol group, balloon compression-induced severe bradycardia was indeed less frequent in patients receiving either atropine or labetalol before compression. Moreover, patients receiving labetalol before compression achieved relatively stable hemodynamics, and none of them suffered from postcompression tachycardia during or after compression.
Therefore, our data indicated that both atropine and labetalol seemed to be effective in decreasing the frequency of severe bradycardia induced by percutaneous microballoon compression for trigeminal neuralgia. This preventive effect seemed to be better with atropine, but there were fewer adverse effects, such as postcompression tachycardia, in the labetalol group. However, neither atropine nor labetalol could completely abolish the occurrence of bradycardia during percutaneous microballoon compression.
The TCR-induced severe bradycardia and succeeding rebound tachycardia are prominent hemodynamic adverse effects of trigeminal ganglion compression. Brown and Preul reported that a significant, abrupt drop in heart rate occurred upon entry of the needle into the foramen ovale, or upon balloon advancement or inflation.4 Dominguez et al reported that the puncture of the foramen ovale caused an abrupt drop in heart rate in 80% of their patients, ganglion compression causing marked tachycardia in all patients and extrasystoles in one-third of patients.7 In line with their findings, transient severe bradycardia and a succeeding rebound tachycardia were also noted in most of our patients.
The detailed mechanisms of TCR remain obscure. Some experiments suggest that the changes in cardiac rhythm may stem from the stimulation of trigeminal nerve fibers with different thresholds. For example, in a report by Kumada et al, a trigeminal depressor response to low-frequency electrical stimulation within discrete sites in the spinal trigeminal complex was described in a rabbit model; they also observed that this converted to a pressor response when the frequency of stimulation was increased.13
Furthermore, Terui et al found that low-frequency electrical stimulation of the A-delta fibers of the rabbit infraorbital nerve induced a depressor response, while increasing the frequency to stimulate the C fibers elicited a pressor response.14 Therefore, it is plausible to expect that the heart rate alteration observed in our patients might have resulted from the complex nerve stimulation during compression, initially by the balloon inflation preferentially stimulating A-delta fibers and later by complete balloon inflation stimulating predominantly the C fibers, resulting in a transient severe bradycardia at the outset and rebound tachycardia afterward.
Current opinions on the arcs of the TCR include the Gasserian ganglion, trigeminal nerve, superficial medullary dorsal horn, sensory nucleus of the trigeminal nerve, short internucial fibers, and motor nucleus of the vagus nerve. The dorsal region of the spinal trigeminal tract contains neurons from both the hypoglossal and vagus nerves, and projections between the vagus and trigeminal nuclei have been reported.10, 15 Thus, vagal stimulation after trigeminal nerve activation likely accounts for the reflexive response of bradycardia. However, the TCR-induced bradycardia still could not be completely blocked by high-dose atropine,16 indicating that complicated interneuronal reflex arcs do exist and may be responsible for the phenomenon. Notably, the TCR-induced cardiac effects were observed in decerebrate animals, suggesting that the TCR circuit is intrinsic to the brainstem.17
In addition to the parasympathetic nervous system, our data indicated that the sympathetic nervous system might also participate in the TCR. In addition, the reflex tachycardia may have a sympathetic component, as some experiments have also demonstrated that stimulation of the trigeminal nucleus was able to evoke adrenal secretion of epinephrine.8 Dominguez et al also found that serum epinephrine and norepinephrine levels increased significantly in patients who received percutaneous microballoon compression of the trigeminal ganglion.7 In the veiled TCR circuit, both the parasympathetic and sympathetic outflow could be modulated by the trigeminal system within the brainstem.18 In addition, there was evidence to demonstrate that activation of catecholamine axons inside the intermediate nucleus tractus solitarii could produce prolonged bradycardia, supporting the idea that the neuronal reflex bradycardia is also sensitive to the localized sympathetic outflow.19
A similar composition of parasympathetic cardiac motorneurons and sympathetic premotor neurons is also present in the TCR-related ventrolateral medulla.20 Recent evidence has also revealed that TCR may increase cerebral blood flow up to twofold,21, 22 which might also increase the intracranial pressure and subsequent hemodynamic responses. Thus, both the parasympathetic and the sympathetic nervous system may participate in the TCR-mediated cardiac rhythm changes, which might partially explain why premedication with either atropine or labetalol was effective in decreasing the frequency of bradycardia in our study.
In terms of the pressure responses, our data demonstrated that the hypertensive effects occurred immediately after compression and the pressure then returned to normal at the end of ganglion compression. Patients receiving labetalol before ganglion compression seemed to have a more stable systemic blood pressure than those receiving atropine. Although Brown et al observed arterial hypotension and bradycardia in patients undergoing percutaneous microcompression of the trigeminal ganglion,4 others conversely found arterial hypertension during the compression, which accorded with what we reported.7, 23, 24 These controversial pressure effects signified that a complicit neuronal circuit was involved in the responses. At present, it is still not clear why a difference exists in patients whose trigeminal neuralgia was treated with mechanical compression or with radiofrequency thermocoagulation.
Obviously, coactivation of the sympathetic and parasympathetic nervous systems may play an important role in the generation of the TCR, and the bradycardia or tachycardia presumably is only a phenomenon that reflects the balance between the parasympathetic and sympathetic outflow.9 It is likely that activation of both sympathetic-mediated peripheral vasoconstriction and parasympathetic-mediated bradycardia produces these complex and unstable hemodynamic changes. It is also plausible to hypothesize that coactivation of the autonomic systems provides a simply observed but difficult to explain hemodynamic effect in terms of trigeminal stimulation and related treatment. This hypothesis can be at least supported by a famous animal study in which TCR-induced coactivation of both the sympathetic and parasympathetic outflow was observed in a decerebrate rabbit model.25
Methods that prevent the trigeminal depressor response have had mixed results. Continuous intraoperative monitoring of hemodynamic parameters is commonly used; it allows the surgeon to interrupt surgical maneuvers immediately upon occurrence of TCR.26 This technique returns the heart rate to normal without the need for additional anticholinergic medication.
Lubbers et al recommended the prophylactic intravenous administration of 0.5 mg atropine immediately before any surgical manipulation that might trigger the TCR.27 However, Prabhakar et al showed that premedication with a vagolytic drug seemed to be insufficient for preventing the TCR during posterior fossa surgery.28 Kuchta et al suggested that premedication with anticholinergics might not be necessary for preventing the trigeminal depressor response.29 They suggested that intravenous atropine was effective for preventing further hemodynamic deterioration.
In addition to atropine, some authors have suggested using ketamine for anesthetic induction to decrease the oculocardiac reflex in children undergoing strabismus surgery.30 In a review of the literature, labetalol was never mentioned for prevention of the trigeminal depressor response. However, the mixed autonomic outflow provides room for the prevention of TCR-induced hemodynamic responses by sympatholytic agents.
5. Conclusion
Taking all the evidence together, we concluded that premedication with atropine or labetalol could decrease the frequency of bradycardia and the degree of change in systemic blood pressure during percutaneous microballoon compression of the trigeminal ganglion. Although the mechanism underlying these hemodynamic changes is not clear, coactivation of the sympathetic and parasympathetic nervous systems provides a plausible explanation for these hemodynamic effects. This report also displays that a complex interneuronal interaction in the TCR possibly exists at the brainstem level. Thus, our study might shed the light on a novel way of thinking about TCR-mediated hemodynamic changes.