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J Physiol Volume 570, Number 2, 421-428, January 15, 2006 DOI: 10.1113/jphysiol.2005.095562
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Acute response to intracisternal bupivacaine in patients with refractory pain of the head and neck

Gavin Lambert1,5, Mikael Elam2, Peter Friberg1, Christopher Lundborg3, Sinsia Gao1, Jonas Bergquist4 and Petre Nitescu3

Departments of
1 Clinical Physiology
2 Clinical Neurophysiology
3 Anaesthesiology (Pain Section), Sahlgrenska Hospital, 413 45 Göteborg, Sweden
4 Department of Analytical Chemistry, Biomedical Centre, Uppsala University, 751 24 Uppsala, Sweden
5 Baker Heart Research Institute, Melbourne, Victoria 8008, Australia


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Continuous intracisternal infusion of bupivacaine for the management of intractable pain of the head and neck is effective in controlling pain in this patient group. With the catheter tip being located at the height of the C1 vertebral body, autonomic regulatory information may also be influenced by the infusion of bupivacaine. By combining direct sampling of cerebrospinal fluid (CSF), via a percutaneously placed catheter in the cisterna magna, with a noradrenaline and adrenaline isotope dilution method for examining sympathetic and adrenal medullary activity, we were able to quantify the release of brain neurotransmitters and examine efferent sympathetic nervous outflow in patients following intracisternal administration of bupivacaine. Despite severe pain, sympathetic and adrenal medullary activities were well within normal range (4.2 ± 0.6 and 0.7 ± 0.2 nmol min–1, respectively, mean ±S.E.M.). Intracisternal bupivacaine administration caused an almost instantaneous elevation in mean arterial blood pressure, increasing by 17 ± 7 mmHg after 10 min (P < 0.01). Heart rate increased in parallel (17 ± 5 beats min–1), and these changes coincided with an increase in sympathetic nervous activity, peaking with an approximately 50% increase over resting level 10 min after injection (P < 0.01). CSF levels of GABA were reduced following bupivacaine (P < 0.05). CSF catecholamines and serotonin, and EEG, remained unaffected. These results show that acutely administered bupivacaine in the cisterna magna of chronic pain sufferers leads to an activation of the sympathetic nervous system. The results suggest that the haemodynamic consequences occur as a result of interference with the neuronal circuitry in the brainstem. Although these effects are transient, they warrant caution at the induction of intracisternal local anaesthesia.

(Received 28 July 2005; accepted after revision 21 October 2005; first published online 27 October 2005)
Corresponding author G. Lambert: Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC 8008, Australia. Email: gavin.lambert{at}baker.edu.au


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The continuous intracisternal infusion of bupivacaine for the management of intractable pain of the head and neck (Appelgren et al. 1996) has yielded an extraordinary improvement in pain management and quality of life for this patient group. With the catheter tip being located at the height of the C1 or C2 vertebral bodies, in the lower part of the cisterna magna, local anaesthetic may impact on the lower seven cranial nerves, and the spinal trigeminal nucleus of the fifth nerve, to impart pain relief. However, important afferent information from visceral organs also travels in some of these cranial nerves (Guyenet, 1990; Spyer, 1990), and several nuclei involved in the processing of autonomic regulatory information (such as the nucleus of the tractus solitarius, and ventromedial and rostral ventrolateral medulla) may also be influenced by the infusion of bupivacaine. Appelgren and coworkers noted that some patients reacted with increased blood pressure following intracisternal bolus doses of bupivacaine (Appelgren et al. 1996). This observation raises the possibility that alterations in autonomic function, including changes in blood pressure and heart rate, may impact on the effectiveness of this therapy.

In order to explore haemodynamic changes in patients with refractory pain of the head and neck during acute intracisternal bupivacaine administration, we combined measurement of sympathetic nervous function with assessment of heart rate and blood pressure response. Simultaneous intracisternal cerebrospinal fluid (CSF) sampling for neurochemical quantification of monoamines and GABA, and EEG monitoring, were also performed.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Results obtained from 16 patients (nine female/seven male, aged 60 ± 3 years, range 34–81) with intractable pain of the head, neck, face, mouth and upper extremities forms the basis of this report. All patients were admitted and treated at the Department of Anaesthesiology (Pain Section) of the Sahlgrenska University Hospital following a prolonged history of refractory pain associated with malignancy in the head and neck region (n= 5); one patient had leukaemia; eight patients had non-cancer-related pain (Table 1); five of the patients were treated for mild hypertension, but had been free from treatment for at least 24 h by the time of testing. The study conformed with the Declaration of Helsinki and was approved by the local ethical and isotope committees at the Sahlgrenska University Hospital. All subjects gave their written informed consent to participate in the study.


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  		Table 1. Patient characteristics
 
Intracisternal cannulation

Studies were performed in conscious subjects immediately following the surgical placement of a thin catheter in the cerebromedullary cistern (cisterna magna) (Appelgren et al. 1996). Intracisternal cannulation was performed in the operating room under general anaesthesia using short-acting anaesthetics, a combination of propofol and fentanyl. Electrocardiogram, heart rate, blood pressure and oxygen saturation (pulse oximetry) were monitored throughout the procedure. During anaesthesia patients were breathing spontaneously using laryngeal masks. In seven subjects, nitrous oxide was added to the anaesthetic mixture during the catheter-insertion procedure. Prior to catheter insertion and tunnelling, carbocaine 10 mg ml–1 was given in the skin. Following dural puncture with a 9 cm 17G Tuohy needle, a clear nylon 1.1 mm o.d., 900 mm 18G catheter with a closed rounded tip and three side holes (Portex 100/382/116, Hythe, UK) was threaded through the needle. The catheter was advanced cranially under C-arm fluoroscopic control until its tip reached the C1 vertebral body (Fig. 1). Catheter position was verified with Omnipaque (Nycomed, Oslo, Norway). In order to prevent headache development associated with CSF spills and catheter placement, 10 ml of sterile saline was slowly infused in all patients. Haemodynamic parameters were monitored and recorded by nurses on the patient record. The catheter was tunnelled subcutaneously paravertebrally over the shoulder and parasternally with the tunnel exit at the level of the third chondrocostal junction. The catheter was secured (Nitescu et al. 1991) and an antibacterial filter filled with 0.5% bupivacaine (Marcaine, AstraZeneca, Södertälje, Sweden) was connected to the catheter hub and capped. General anaesthesia was stopped and patient recovery was monitored.



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  		Figure 1.  C-arm fluoroscopic image of catheter with metal guide wire
The position of the catheter tip is indicated by the arrow, and the level of the C1 vertebral body is shown by the white dot.

 
CNS and sympathoadrenal assessment

All experiments were performed in conscious subjects following recovery from the surgical procedure. In order to assess noradrenergic and adrenergic nervous function, catecholamine kinetic determinations were made by isotope dilution during a steady-state infusion of a tracer dose of noradrenaline and adrenaline, respectively (Esler et al. 1979). This procedure allowed measurement of catecholamine clearance and calculation of total-body noradrenaline and adrenaline spillover. Blood samples were obtained from an indwelling arterial catheter, and the infusion of tritiated noradrenaline was via a peripheral hand vein. Following procurement of resting data, a bolus injection of bupivacaine (5 mg over 1 min) was made via the intracisterna magna catheter. Intra-arterial blood pressure, heart rate and EEG were continuously monitored. EEG was monitored with standard leads (FP1, F3, T3, T5, O1, FP2, F4, T4, T6, O2) and was used to monitor cortical function in general, and putative changes in the level of wakefulness/attention in particular. Simultaneous blood sampling for catecholamine kinetic determination (10 ml), and CSF (2 ml) for neurochemical and bupivacaine concentration estimations, were obtained at rest and at 10 min following bupivacaine administration. Blood samples were collected into ice-chilled tubes containing EGTA and glutathione. Plasma was separated by centrifugation and stored at –80°C until assayed. Cerebrospinal fluid samples were also collected into ice-chilled tubes containing EGTA, aliquoted into 200 µl fractions, and stored at –80°C until assayed.

Biochemical analyses

Cerebrospinal fluid and plasma monoamine neurochemical concentrations were determined by HPLC coupled with electrochemical detection according to established techniques (Lambert et al. 1993, 1995a,c). Briefly, catecholamines were extracted from plasma, CSF and samples of radiotracer infusate (10 µl) using alumina adsorption and separated by HPLC. Timed collection of eluate leaving the electrochemical cell permitted separation of labelled noradrenaline for subsequent counting by liquid scintillation spectroscopy. In CSF samples, the acidic metabolites of serotonin and dopamine, 5-hydroxyindoleacetic (5-HIAA) and homovanillic acids (HVA), and the deaminated and O-methylated metabolite of noradrenaline, 3-methoxy-4-hydroxyphenylglycol (MHPG), were deproteinated using an ultrafiltration membrane (Microcon 30, Amicon, Beverly, MA, USA) and injected directly onto the HPLC system. The chromatographic system consisted of a Model 480 High Precision Pump, Model Gina autosampler, Model STH 585 column oven, Chromeleon 3.03 Chromatography Data System (Dionex, Germering, Germany), Model 5100A coulometric detector equipped with a Model 5021 conditioning cell and a Model 5011 analytical cell (Environmental Sciences Associates, MA, USA) and a 25 cm Altex Ultrasphere column (ODS 4.6 mm x 25 cm, 5 µm particle size; Beckman Instruments, Inc., CA, USA). Analysis was performed at 24°C with the operating potentials set according to established methods (Lambert et al. 1993, 1995a,c).

CSF bupivacaine concentrations were also determined by HPLC with coulometric detection. The system was identical to that used for catechol analysis, except that the operating potentials were set at 0 V for the guard cell and +0.6 and 0 V for detectors 1 and 2, respectively. All measurements were made using the oxidizing potential applied at detector 1, and bupivacaine was identified by its retention behaviour compared to that of an authentic standard solution. The mobile phase, delivered at a flow rate of 1.0 ml min–1, consisted of 50–60% acetonitrile and 20 mM NaH2PO4, pH 7.0.

Concentrations of {gamma}-aminobutyric acid (GABA) in CSF were determined by capillary electrophoresis with laser-induced fluorescence detection (Bergquist et al. 1994). Data were obtained using a sampling rate of 5 Hz, and processing and analysis were performed using the System Gold software package (Beckman). Peaks were identified by both their electrophoretic mobility, and by spiking samples with standard solutions of GABA. GABA was subsequently quantified using linear calibration plots based on peak area versus concentration. Each calibration consisted of six different concentrations, spanning the range of concentrations found in CSF samples. Detection limits were estimated at two times the peak-to-peak noise by extrapolation from plots of peak height versus concentration. The detection limit for GABA was 0.29 nM.

Statistical analysis

All results, unless otherwise specified, are expressed as means ± standard error of the mean (S.E.M.). The influence of intracisternal bupivacaine was evaluated using ANOVA. The null hypothesis was rejected if a two-tailed P value was less than 0.05. The possible relation between variables was evaluated using least-squares linear regression analysis, and the correlation coefficients were calculated.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During catheter placement, the intracisternal injection of saline was not associated with any change in blood pressure or heart rate. Following the surgical positioning of the catheter in the cisterna magna and recovery from anaesthesia, the control rate of whole-body noradrenaline spillover to plasma was 4.2 ± 0.6 nmol min–1 and the rate of adrenaline secretion was 0.7 ± 0.2 nmol min–1. Resting blood pressure and heart rate were 152 ± 6/76 ± 4 mmHg and 76 ± 3 beats min–1, respectively.

The rate of spillover of noradrenaline to plasma increased by 52 ± 21% in response to intracisternal bupivacaine (Fig. 2). There was a trend for the rate of adrenaline secretion to be elevated following bupivacaine administration (0.7 ± 0.2 vs. 1.7 ± 0.6 nmol min–1, P= 1.1). The most common response, observed in 12 of the 16 patients, was for sympathetic nervous activity, blood pressure and heart rate to be increased 10 min following bupivacaine administration (Fig. 2). The alteration in sympathetic nervous activity mirrored the change in heart rate and blood pressure (Fig. 3). Mean arterial pressure was increased by 17 ± 7 mmHg (P < 0.05) and heart rate was increased by 17 ± 5 beats min–1 (P < 0.05).



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  		Figure 2.  Whole-body sympathetic nervous activity, heart rate and mean arterial blood pressure
Measurements were taken at rest (Con) and 10 min post-intracisternal bupivacaine (Bup) in patients with intractable pain of the neck and head regions. NA, noradrenaline; bpm, beats min–1. *P < 0.05.

 


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  		Figure 3.  Hemodynamic changes following bupivacaine
The relation between change in whole body rate of spillover of noradrenaline to plasma and the change in mean blood pressure (left) and heart rate (right) in response to intracisternal bupivacaine. The continuous line indicates the line of best fit, and the dotted lines signify 95% confidence intervals of data.

 
The effect of bupivacaine was transient, with haemodynamic parameters returning to their control level after 30 min (blood pressure and heart rate were 155 ± 9/77 ± 5 mmHg and 70 ± 3 beats min–1, respectively, and the rates of spillover of noradrenaline to plasma and adrenaline secretion were 4.2 ± 0.7 and 0.8 ± 0.3 nmol min–1, respectively). The CSF concentrations of bupivacaine at 10 and 30 min post-injection were 71 ± 26 and 7 ± 1 µg ml–1, respectively. The CSF concentration of bupivacaine was not associated with the degree of sympathetic nervous activation.

Intracisternal catecholamines and their metabolites remained unchanged following intracisternal bupivacaine and were not related to the prevailing level of blood pressure or sympathetic nervous activity (Table 2). While the CSF concentration of the serotonin metabolite 5-HIAA also remained unchanged in response to bupivacaine, the inhibitory neurotransmitter GABA CSF concentration was reduced 10 min following local anaesthetic administration (Table 2, P < 0.05). The change in CSF GABA concentration was not significantly related to the change in sympathetic activity, heart rate or blood pressure (all r= 0.01, P= 0.98).


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  		Table 2. Cerebrospinal fluid neurochemical concentrations in response to bupivacaine
 
Judged by the EEG frequency distribution, the majority of patients were fully awake throughout the experimental procedure, whereas four patients were mildly drowsy. The average postcentral rhythm was 8.5 Hz (range 6–12) before administration of the intracisternal blockade, and remained unaltered after bupivacaine administration in all but two patients. These two patients, in whom sympathetic activity was increased by 66 and 53%, respectively, showed a transient increase in low frequency EEG activity 5–15 min after the bupivacaine administration. No patient showed increased EEG frequency following the bupivacaine administration, or any EEG desynchronization at the time of administration.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the majority of our patients with intractable pain of the head and neck, the acute administration of intracisternal bupivacaine was associated with substantial alterations in blood pressure and heart rate. The observation that in most patients blood pressure and heart rate were elevated, whilst in a few they were reduced, indicates that intracisternally administered bupivacaine may exert divergent effects by acting on different regions in the brainstem (Fig. 4). Furthermore, our results show that the haemodynamic sequelae following bupivacaine administration arise as a result of substantial changes in the degree of sympathetic nervous activity. While the development and application of the technique of chronic intracisternal bupivacaine administration has proven effective in the management of pain in well-characterized pain sufferers, the results of the present report indicate that bolus doses of bupivacaine via this route of administration must be used with caution, since high concentrations of intracisternal local anaesthetics may lead to increased risk of cardiovascular complications, including stroke and sympathetically mediated tachyarrhythmias.



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  		Figure 4.  Hypothetical mechanism of action of bupivacaine at the level of the medulla
The schema takes into account the divergent haemodynamic response evident after intracisternal bupivacaine administration. NTS, nucleus of the tractus solitarius; RVLM, rostral ventrolateral medulla; CVLM, caudal ventrolateral medulla; IML, intermediolateral column of the spinal cord; + and – represent stimulatory and inhibitory inputs, respectively.

 
In the majority of patients, intracisternal bupivacaine was associated with an almost immediate sympathoexcitation. While we cannot unequivocally rule out the effect of local volume expansion upon bupivacaine injection as a possible contributing factor, we feel that this is unlikely given that injection of saline during surgery was not associated with any alteration in blood pressure or heart rate. While induction of anaesthesia with propofol is associated with a reduction in muscle sympathetic nerve activity and blood pressure, reflex activation of the sympathetic nervous system during propofol anaesthesia, in the presence of fentanyl, is not abolished (Pacentine et al. 1995). Indeed, the observation that muscle sympathetic nerve activity retains its normal pulse synchronous pattern during propofol anaesthesia indicates that modulation of sympathetic outflow from arterial baroreceptors is present (Sellgren et al. 1990, 1994). The unaltered EEG pattern throughout the experimental procedure argues against generalized effects on cerebral function, or shifts in wakefulness, underlying the results. Specifically, the complete absence of EEG desynchronization following the administration of intracisternal bupivacaine argues against increased attention/psychological stress underlying the sympathetic activation occurring in the majority of our patients (Bischoff, 1994). In fact, 2 out of 16 patients showed a transient increase of EEG activity in the lower frequency range, indicating sedation. Although a pharmacological effect on brainstem centres controlling the sleep/waking cycle cannot be ruled out, the fact that such reduced EEG frequency was only observed in two of our patients suggests that this finding reflects a spontaneously occurring tiredness during the experiment. Additionally, the observation that CSF catecholamine levels remain unchanged following bupivacaine seems to preclude activation of forebrain sympathoexcitatory neurones as the possible cause. Previous studies, conducted in human subjects, have illustrated some dependence of sympathetic nervous outflow on central noradrenergic activity (Lambert et al. 1997, 1998) and have provided evidence of a relationship between subcortical noradrenergic neuronal activity and renal sympathetic activation in essential hypertension (Ferrier et al. 1993) and cardiac sympathetic activity in heart failure (Lambert et al. 1995b; Aggarwal et al. 2002). Our results support the possibility that the haemodynamic consequences arising following acute intracisternal bupivacaine occur as a result of interference with the neuronal circuitry at the brainstem level (Fig. 4). A blockade of baroreceptor afferents travelling in cranial nerves VII, IX and X is an obvious possible mechanism. An alternative/additional mechanism may entail a direct hyperpolarizing effect of bupivacaine on neurones emanating from the nucleus of the tractus solitarius, leading, in the majority of cases, to a change in the tonic inhibition of sympathetic preganglionic fibres.

One of our patients showed a reduction in sympathetic nervous activity following intracisternal bupivacaine administration, and this was paralleled by marked reductions in blood pressure and heart rate, in stark contrast to the average response of the study group. Additionally, in one patient not included in the present analysis because of concurrent antidepressant use (amitriptyline hydrochloride), we observed an over 50% reduction in the rate of spillover of noradrenaline to plasma, 13 beats min–1 heart rate reduction, and a fall in mean arterial blood pressure of 36 mmHg in the acute stage following intracisternal bupivacaine. These diverging sympathetic and haemodynamic responses following bupivacaine appeared not to be due to the initial level of blood pressure or sympathetic activity, pain aetiology, previous or current therapy, or differences in clearance of bupivacaine from the injection site. The most likely explanation for the divergent haemodynamic responses in patients is that the bupivacaine was acting on different brainstem regions as a result of either subtle variation in catheter placement, or alteration in the spread of the drug (Fig. 4). Given that bupivacaine is able to penetrate nervous tissue to provide a profound nerve block (Hocking & Wildsmith, 2004), it is possible that the few cases with reduced sympathetic activity and blood pressure may result from a blockade of bulbospinal sympathoexcitatory fibres from the ventrolateral medulla, overriding/abolishing the sympathoexcitation elicited by afferent blockade. Experimental studies in rabbits have demonstrated that injection of drugs into the fourth ventricle can induce an increase in the number of Fos-positive neurones in a number of brain regions, including the nucleus of the tractus solitarius, and in the rostral, intermediate, and caudal parts of the ventrolateral medulla (Hirooka et al. 1996).

In this study, we observed substantial alterations in sympathetic nervous activity, whereas adrenomedullary function was only modestly influenced following intracisternal bupivacaine. Such disconnection between sympathetic and adrenal medullary secretion is not without precedent. In patients with essential hypertension, sympathetic inhibition following treatment with the imidazoline-binding agent rilmenidine is not accompanied by alterations in the rate of adrenaline secretion (Esler et al. 2004). In anaesthetized and ventilated rats, the discharge of sympathetic regulatory neurones in the rostral ventrolateral medulla controlling adrenaline secretion is modulated by a tonic neural inhibition that arises from a source that is different from the sympathoinhibitory neurones in the caudal ventrolateral medulla that project to rostral ventrolateral medulla sympathetic premotor neurones controlling vasoconstrictor and cardiac targets (Natarajan & Morrison, 1999; Morrison & Cao, 2000).

The majority of our patients suffered from neuropathic pain, a condition often considered to be aggravated by sympathetic activation or peripheral adrenoceptor stimulation (Nathan, 1947; Richards, 1967; Roberts, 1986; Janig & Stanton-Hicks, 1996). Despite the marked sympathetic activation elicited in the majority of patients receiving intracisternal bupivacaine, none of our patients reported increased pain after injection. Although the sensory block induced by bupivacaine may cancel out a pain augmentation induced by the acute sympathoexcitation, patients with a pain distribution reaching outside the area affected by the sensory block did not experience increased pain from areas outside the sensory block. This observation is in line with the growing scepticism concerning the concept of sympathetically maintained pain (Verdugo & Ochoa, 1994; Schott, 1995; Max & Gilron, 1999; Elam, 2001).

Treatment of intractable pain remains a major challenge in medicine, and the intracisternal administration of bupivacaine has been demonstrated to be effective in alleviating pain of the head and neck in well-characterized patients (Appelgren et al. 1996). The present results indicate that bolus doses of local anaesthesia via this route of administration should be used with caution, due to potential effects on autonomic nervous system homeostasis. However, these effects are transient and while acute sympathetic nervous activation may be associated with ventricular tachyarrhythmias and myocardial infarction, particularly in those with underlying coronary artery disease, we have not observed a single case of severe cardiac complications in the acute phase following bupivacaine administration. Although this study has provided some insight into the central nervous system pathways regulating sympathetic and adrenal medullary activity it should not discourage the careful use of intracisternal blocks in patients with otherwise intractable pain in the head or neck region.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 
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   Acknowledgements
 
The Swedish Society for Medical Research, the Swedish Medical Research Council (project nos. 13123, 621-2002-5261 and 12170) and grants from Sahlgrenska University Hospital supported this study. Jonas Bergquist has a senior research position from the Swedish Research Council, and Gavin Lambert is supported by grants from the National Health and Medical Research Council of Australia.





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