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Keywords:

  • autonomic dysreflexia;
  • capsaicin;
  • detrusor hyper-reflexia;
  • spinal cord injury

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

OBJECTIVES

To determine whether capsaicin-sensitive nerves in the bladder form the afferent limb involved in autonomic dysreflexia (AD) in patients with spinal cord injury (SCI).

PATIENTS AND METHODS

Seven men with SCI (five cervical cord, two thoracic cord) with AD and detrusor hyper-reflexia (DH) were enrolled. Under general anaesthesia, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol) was instilled in the bladder and retained for 30 min. The patients were assessed by medium-fill cystometry (CMG) just before and 50 min after the capsaicin treatment. Intra-arterial blood pressure (BP) and heart rate were monitored continuously throughout the procedure; 10% ethanol was instilled before capsaicin treatment in four patients as a control. Serum catecholamines were measured during bladder filling and capsaicin treatment, and the blood ethanol concentration also measured after instillation in all patients. The CMG with concomitant monitoring of BP and heart rate was repeated 1 week, 1, 3, 6, 12 and 24 months after instillation. In two patients the instillations were repeated 5 and 12 months after the first because of recurrence of DH. Urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of uninhibited detrusor contraction (UICmax), the bladder capacity at 40 cmH2O detrusor pressure (Cdp40) and a systolic BP of> 140 mmHg or diastolic BP of> 90 mmHg (CHT).

RESULTS

There was an increase in BP and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. Instillation of capsaicin produced a significant increase in both systolic and diastolic BP and a significant decrease in heart rate. The maximum cardiovascular effects were at 5–10 min after instillation and gradually returned to baseline within 40 min. The vehicle had negligible effects on either BP or heart rate. After capsaicin treatment, the responses of BP and heart rate to bladder distension were significantly reduced. Both serum catecholamine values and the blood ethanol concentration remained within normal limits. The mean (range) follow-up after the first treatment was 15 (6–30) months. One month after treatment all seven patients became continent and their episodes of AD became negligible and well tolerable between catheterizations (for 3–4 h); the effects lasted for ≥ 3 months in all. MCC was significantly increased at 4 weeks and 3 months, and UICmax significantly decreased at 4 weeks after treatment. Both mean Cdp40 and CHT increased 1 week, 1 and 3 months after treatment. Two patients received a second instillation, and have been continent with no symptomatic AD for 6 and 24 months. The remaining five patients have been continent with no symptomatic AD for 6–12 months.

CONCLUSION

These results indicate that intravesical capsaicin, but not the vehicle, acutely triggers AD in patients with SCI, suggesting involvement of bladder capsaicin- sensitive afferents in AD in these patients. The results also suggest that intravesical capsaicin may be a promising therapy for both AD and DH in such patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Autonomic dysreflexia (AD) commonly affects patients with spinal cord injury (SCI) and lesions above T7 [1]. Attacks of AD result from unchecked reflex sympathetic outflow, which develops in response to stimuli below the level of the spinal cord lesion, most often from the urinary bladder [2]. The development of AD represents a medical emergency, where the consequences may be significant morbidity or death [3], and acts as a limiting factor when clean intermittent catheterization (CIC) is introduced in these patients. Giuliani et al.[4] reported that in chronic spinalised rats rapid distension of the bladder with saline produced transient tachycardia, hypertension and positive cardiac inotropism, which were similar to those evoked by applying capsaicin on the outer surface of the bladder. In addition, these responses were not apparent in rats systemically pretreated with capsaicin. These findings suggest that some bladder afferents susceptible to capsaicin desensitization are involved in the development of AD in spinalised rats. However, the precise mechanisms responsible for AD in patients with chronic SCI have not been clarified. Intravesical instillation of capsaicin and resiniferatoxin, an ultrapotent capsaicin analogue, has been reported to suppress detrusor hyper- reflexia (DH) in patients with spinal cord lesions [5–11]. The present study was designed to determine whether bladder capsaicin-sensitive nerves play a role in the afferent limb of AD in patients with SCI. The clinical efficiency of intravesical capsaicin on DH and AD in such patients was also investigated.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Seven men with traumatic SCI, including five with cervical and two with thoracic cord injuries, and with AD and DH, were enrolled in the study, which was approved by the Ethics Committee of the authors’ institution. The objective and possible side-effects of treatment were explained to the patients, who provided written informed consent after a clear explanation that capsaicin was being used as a chemical, not a medicine, and had no certification for use in humans.

Table 1 summarizes the characteristics of the patients; the spinal lesions were complete in all seven patients. All had severe urinary incontinence and AD refractory to oral antimuscarinic drugs and α-adrenergic blockers. Before starting the study, all patients completed a frequency/volume chart for at least 3 days on which each voided volume and episodes of incontinence and symptoms related to AD, e.g. sweating, headache and facial flush, were recorded. The patients were also assessed by a video-urodynamic study. A 12 F double-lumen catheter was placed transurethrally in the bladder and a balloon catheter placed in the rectum to record abdominal pressure. The bladder was filled with room-temperature contrast medium containing 30% iodine at 30 mL/min. During the filling cystometric study, blood pressure and heart rate were simultaneously monitored to detect AD induced by bladder filling. DH and AD were detected in all patients, but no patient had VUR during the video-urodynamic study. Because of severe AD, four patients had a suprapubic cystostomy and another was managed with a urethral indwelling catheter.

Table 1.  Clinical and urodynamic details before treatment of seven patients (all men) with spinal cord injury treated with intravesical capsaicin, and the changes in MCC and UICmax after treatment
VariablePatient no.Mean (sem)
1234567
  1. Duration, duration from injury; Ureth. cath, transurethral indwelling catheter; BPs, BPd, systolic and diastolic blood pressure; Empty, empty bladder; Full, full bladder. *P < 0.05 from pretreatment value, paired Student's t-test. NE, not examined, †not detected.

Age, years  24  34  27  23  18  32  52 
Injury level (duration, years)C6 (5.1)T3 (16.9)C7 (9.5)C6 (1.5)C6 (1.2)T5 (7.2)C7 (5) 
ManagementCystostomyCIC, padsTrigger/padsCystostomyUreth. cathCystostomyCystostomy 
MCC, mL  25150  80250  42234146132.4 (33.5)
UICmax, cmH2O  75  63100  95  93  65  31  74.6 (9.2)
Detrusor compliance, mL/cmH2O    6.4  15.0    6.2    3.4    2.8    7.8    2.2 
BPs/BPd, mmHg
Empty  90/60126/83130/70104/56  99/55117/60135/80 
Full179/92159/95154/70166/81152/99170/94191/97 
Heart rate, beats/min
Empty  81  79  95  61  63  64  61 
Full  62  63  88  41  59  57  65 
With time after treatment
MCC, mL
1 week  70220105390450300147240.3 (54.9)
4 weeks300240370400550370180344.3* (45.4)
3 months250220400NE590450NE382.0* (151.6)
UICmax, cmH2O
1 week  75  55  95  60  46  70  25  60.8 (8.4)
4 weeks  60  45  58  45  18  52  18  42.3* (6.6)
3 months  80  48  63NE    0  40NE  46.2 (13.4)

Capsaicin (Sigma Chemical Co., St. Louis, MO) was dissolved in absolute ethanol to give a 20 mmol/L stock solution the night before treatment (about 12 h before instillation). The solution was kept in a refrigerator (4°C) and diluted in saline just before use to a concentration of 2 mmol/L. The solution was instilled in the operating theatre; general anaesthesia was induced with a short-acting barbiturate and maintained with fentanyl and a mixture of oxygen, nitrous oxide and isoflurane. Atropine was not used either before or during the procedure. The intra-arterial blood pressure and heart rate were monitored continuously via a catheter introduced into the left radial artery throughout the procedure. Under general anaesthesia, a 12 F double-lumen catheter was placed in the bladder transurethrally and a balloon catheter in the rectum. The patients underwent filling cystometrography with instillation of room-temperature saline at 30 mL/min immediately before capsaicin treatment, to confirm that anaesthesia was sufficient to suppress DH during bladder filling. After the bladder was emptied, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol/saline) was instilled into the bladder by manual infusion using a polyethylene syringe for 2 min, and retained for 30 min. Cystometrography and concomitant recording of intra-arterial pressure and heart rate were repeated 50 min after the start of capsaicin instillation (i.e. 20 min after withdrawing the capsaicin solution). In four of the seven patients 10% ethanol (vehicle only) was also instilled before capsaicin as a control. Blood was sampled from the arterial catheter before and at the end of bladder filling, and just before and 15, 30, 60, 90, 120 min after the beginning of capsaicin instillation, to measure serum catecholamines (adrenaline, noradrenaline and dopamine) and blood ethanol concentration after capsaicin instillation. A Foley catheter (14 F) was placed in the bladder after the second cystometrography and removed 1 day after treatment; all patients were then managed by CIC.

All patients were followed at 1 and 4 weeks and 3 months after capsaicin treatment, and every 3 months thereafter. At each follow-up visit, urinary symptoms were evaluated and cystometrography with concomitant monitoring of blood pressure and heart rate repeated using the same methods as before treatment. Prophylactic antibiotics were given after capsaicin instillation and after cystometrography. In two patients the capsaicin instillation was repeated 5 and 12 months after the first because of recurrence of DH. The urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of the uninhibited detrusor contraction (UICmax), the bladder capacity when the detrusor pressure reached 40 cmH2O (Cdp40) and the bladder capacity when systolic blood pressure reached 140 mmHg or diastolic blood pressure reached 90 mmHg (CHT).

The results are presented as the mean (sem) and were analysed statistically using a paired Student's t-test for comparisons between before and after treatment, with P < 0.05 considered to indicate significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

There was an increase in blood pressure and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. There was a significant increase in both systolic and diastolic pressures and a significant decrease in heart rate during capsaicin instillation (Fig 1a,b). These effects were pronounced at 5–10 min after instillation and gradually subsided within 40 min. No significant detrusor contractions developed during capsaicin treatment. The vehicle had negligible effects on either blood pressure or heart rate in all four patients tested. Bladder distension significantly (P < 0.001, t-test) increased the mean blood pressure (mmHg) before capsaicin treatment, at 62.7 (4.3) empty and 96.4 (6.5) full, but this response was significantly (P < 0.01) attenuated after treatment to 65.8 (4.6) empty and 79.8 (5.1) full (P = 0.08).

imageimage

Figure 1. The effects of intravesical instillation with capsaicin (circles) and vehicle (squares) on intra-arterial blood pressure (a; systolic open symbols, diastolic closed symbols) and heart rate (b) in patients with AD caused by chronic SCI. Significant differences from pretreatment values are *P < 0.05 and **P < 0.01, respectively, paired Student's t-test.

Both serum catecholamine values and the blood ethanol concentration remained within normal limits throughout at all sampling times. All patients reported an initial deterioration in their symptoms within ≈ 2 weeks after treatment, followed by a clinical improvement. Four weeks after treatment all seven patients became continent and their episodes of AD negligible and well tolerable between CIC (for 3–4 h). The mean (range) follow-up after the first treatment was 15 (6–30) months. The effects persisted for at least 3 months in all patients. The MCC was significantly increased 4 weeks and 3 months after treatment, and UICmax significantly decreased 4 weeks after treatment (Table 1). Both mean Cdp40 and CHT significantly increased 1 week, 1, 3 and 6 months after treatment (Fig. 2a,b). Two patients (1 and 2) who received a second instillation have been continent with no symptomatic AD for 6 and 24 months; the remaining five patients have been continent with no symptomatic AD for 6–12 months.

imageimage

Figure 2. Changes in Cdp40 (a) and CHT (b) with time after intravesical instillation with capsaicin. Significant differences from pretreatment value at *P < 0.05 or **P < 0.01, paired Student's t-test.

DISCUSSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

The present study shows that intravesical capsaicin, but not vehicle (10% ethanol) can induce AD, characterized by increased blood pressure and paradoxical bradycardia in patients with SCI and symptomatic AD. Moreover, the increase in mean blood pressure in response to bladder distension was significantly suppressed immediately after capsaicin instillation. These findings suggest that capsaicin-sensitive afferents are important in the pathophysiological mechanisms that cause the AD in patients with SCI. It is unlikely that an increase in intravesical pressure contributes to the capsaicin-induced AD, as no detrusor contractions were detected during treatment. Geirsson et al.[6] reported that AD symptoms developed in patients with complete spinal cord lesions during intravesical instillation with capsaicin. These authors found that only one of the three patients evaluated had a small phasic contraction during capsaicin treatment. The findings are in accordance with those in the present study. In their series, three of 10 patients treated with capsaicin had had previous episodes of AD, which successfully resolved after capsaicin treatment.

Nerves containing C-fibres transmit nociceptive information into the CNS and participate in various reflex responses [12]. These nerves carry receptors that bind capsaicin, recently identified as the vanilloid receptor subtype 1 (VR1) [13]. Excitation of these cells by capsaicin is followed by a lasting refractory state, termed desensitization. VR1-expressing cells have been detected in the brain and dorsal root ganglia [14,15]. More recently, the presence of mRNA encoding VR1 was reported not only nerve fibres running in the suburothelial layer but also in the urothelial cells in the rat and human urinary bladder [16,17]. Birder et al.[16] showed that exogenously applied vanilloids increase intracellular Ca2+ and evoke nitric oxide release in urothelial cells. Taken together, these findings suggest that urothelial cells work in concert with underlying capsaicin-sensitive afferent nerves to detect irritant stimuli. Therefore, possibly capsaicin, instilled intravesically, acts directly either on VR1 in the bladder urothelial cells or underlying capsaicin-sensitive afferent nerves, which cause AD during treatment.

Although the mechanisms underlying the emergence of AD in patients with SCI are unclear, it has been proposed that the increase in blood pressure elicited by bladder filling is mediated by activation of bladder afferents, which facilitates sympathetic nerve outflow via spinal reflexes and causes vasoconstriction or cardiac stimulation [1,18]. Previous experiments in anaesthetized neurologically intact rats showed that arterial pressure response to bladder distension was reduced by systemic pretreatment with capsaicin (125 mg/kg subcutaneous, 4 days earlier) or by acute or chronic (4 days earlier) intravesical administration of resiniferatoxin (100–1000 nmol/L) [19,20]. Giuliani et al.[4] showed that in acute spinalised rats (C2–C3), rapid distension of the bladder with saline produced transient hypertension, tachycardia and an increase in cardiac contractility similar to those evoked by topical application of capsaicin. These cardiovascular responses were not observed in rats systemically pretreated with capsaicin. These findings in rats are in line with those in the present patents with SCI, suggesting the involvement of capsaicin-sensitive afferents in AD induced by bladder distension.

In the present study the serum concentration of catecholamines, including noradrenaline, remained low even when AD was elicited by either bladder distension or intravesical capsaicin treatment, suggesting negligible roles of circulating catecholamines for AD. Mathias et al.[21] studied the role of plasma catecholamines during AD in quadriplegics, reporting that plasma noradrenaline was three times higher during AD than in the resting state. However, they concluded that this threefold increase might not cause AD as they also found that when L-noradrenaline was injected into these patients to raise the bladder pressure to the level of AD, the plasma noradrenaline level was 21 times higher than that obtained during AD.

AD evoked by bladder distension was reduced immediately after capsaicin instillation, whereas both the onset of improvement of urinary symptoms presumably related to DH and those of urodynamic effects was at> 1 week after treatment. The reasons for this discrepancy in the onset between the inhibitory effect on AD and that on DH are uncertain. Even though both of these abnormal reflexic responses to bladder distension are mediated through capsaicin-sensitive nerves, it is possible that the subpopulation of afferent nerves contributing to the AD response to bladder distension may differ from that contributing to DH.

An important concern about intravesical capsaicin instillation is the adverse effects related to its acute stimulatory effect proceeding to desensitization. Such adverse effects have been reported [5–9] and include a suprapubic burning sensation, urgency and hot flushes during the procedure, and the suprapubic pain, gross haematuria and exacerbation of urinary incontinence within 2 weeks afterward. Although these side-effects are transient and then generally followed by benefit, this limits the practical routine use of capsaicin. Alternatively, resiniferatoxin has been more recently used in the intravesical treatment of overactive bladder and reported to have a similar therapeutic effect on it, but with fewer acute stimulatory side-effects than capsaicin [10,11]. Further studies are needed to determine whether resiniferatoxin has a suppressive effect on AD comparable with that of capsaicin.

In conclusion, the present study shows that intravesical capsaicin, but not vehicle, can produce AD in patients with SCI, suggesting involvement of bladder capsaicin-sensitive afferents in AD in such patients. The present results also suggest that intravesical capsaicin is a promising therapy for both AD and DH in these patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

This work was supported by Grant-in-Aid 13671641 for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture of the Japanese Government. The authors thank Dr William D. Steers for his critical review of this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSIONS
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
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Abbreviations
SCI

spinal cord injury

AD

autonomic dysreflexia

CIC

clean intermittent catheterization

DH

detrusor hyper-reflexia

MCC

maximum cystometric capacity

UICmax

maximum amplitude of the uninhibited detrusor contraction

Cdp40

bladder capacity at detrusor pressure of 40 cmH2O

CHT

bladder capacity at systolic blood pressure of 140 mmHg or diastolic of 90 mmHg.