Autonomic dysreflexia: Current pharmacologic management.

BACKGROUND: Autonomic dysreflexia (AD) is a frequent complication of spinal cord injury (SCI), though current clinical practice patterns for medication management of this condition are unknown. Correspondingly, it is unclear if national differences in practice patterns exist. OBJECTIVE: To determine trends in current pharmacologic management of AD throughout the Americas. DESIGN: International survey of current physician practice patterns. SETTING: Academic medical center. PARTICIPANTS: Sixty physicians managing patients with SCI and prescribing medications to manage AD. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Presence of a formal pharmacologic AD management protocol, first- and second-line medications, patient characteristics influencing pharmacologic management. RESULTS: The majority of physicians (69%) had a formal AD management protocol for inpatient care, with nitroglycerin ointment (82%) being the most common first-line medication. Strong national differences existed regarding the use of nitroglycerin ointment, with 98% of U.S.-based physicians using this as first-line medication and 0% of physicians in Canada or Latin America using this due to recent lack of medication availability. Only 67% of physicians had a preferred second-line medication, with preferences split between hydralazine (48%) and nifedipine (28%). A systolic blood pressure threshold for pharmacologic management was used by 56% of physicians, wheres 26% considered neurological level of injury in decisions to use medications for AD. Heart rate was used by only 5% of physicians in their decision to manage AD with medications. CONCLUSIONS: As of 2023, U.S.-based physicians caring for individuals with SCI largely have formal inpatient protocols in place for medication management of AD, with nearly all relying on nitroglycerin ointment as their first-line medication. In areas outside of the United States where nitroglycerin ointment is unavailable, pharmacologic practice patterns significantly differ.

[Efficacy of fesoterodine for prevention of autonomic dysreflexia in patients with neurogenic dysfunction of the bladder after spinal cord injury].

AIM: to evaluate the effectiveness of fesoterodine for the prevention of autonomic dysreflexia (AD) in patients with neurogenic bladder dysfunction (NBD) after spinal cord injury (SCI). MATERIALS AND METHODS: a total of 53 patients with AD were included in the study. In the main group (n=33) patients received fesoterodine 4 mg per day for 12 weeks as a treatment for neurogenic bladder dysfunction and prevention of AD. In the control group (n=20), patients were monitored for 12 weeks without specific treatment. The assessment was based on the results of ADFSCI and NBSS questionnaires, daily blood pressure monitoring with the completion of a self-observation diary, cystometry with simultaneous monitoring of blood pressure and heart rate. RESULTS: In the main group there was a significant decrease in episodes and severity of AD according to ADFSCI questionnaire and an improvement in the quality of life according to NBSS questionnaire compared to the control group (p<0.001). Also, in the main group, the number of episodes of AD and systolic blood pressure decreased. The maximum bladder capacity and bladder compliance increased (p<0.001), and the maximum detrusor pressure and systolic blood pressure when the cystometric capacity was reached, decreased significantly (p<0.001) in the main group compared in comparison with the control group. CONCLUSION: Fesoterodine at a dosage of 4 mg for 12 weeks reduced the severity of symptoms of AD in patients with SCI and NBD, which was manifested by the stabilization of blood pressure and a decrease in the number of episodes of AD, which significantly improved the quality of life. Also, the drug led to a significant improvement in urodynamic parameters during cystometry, in the form of a decrease in detrusor pressure and an increase in cystometric capacity. We can conclude that fesoterodine is effective in the prevention of AD in patients with NBD after SCI.

Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats.

STUDY DESIGN: Preclinical pharmacology. OBJECTIVES: To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats. SETTING: University laboratory in Pennsylvania, U.S.A. METHODS: Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents. RESULTS: Subcutaneous (SC) administration of 10-30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses. CONCLUSIONS: The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

Clinical trial of home blood pressure monitoring following midodrine administration in hypotensive individuals with spinal cord injury.

BACKGROUND: Individuals with spinal cord injury (SCI) above thoracic level-6 (T6) experience impaired descending cortical control of the autonomic nervous system which predisposes them to blood pressure (BP) instability, including includes hypotension, orthostatic hypotension (OH), and autonomic dysreflexia (AD). However, many individuals do not report symptoms of these BP disorders, and because there are few treatment options that have been proven safe and effective for use in the SCI population, most individuals remain untreated. OBJECTIVE: The primary aim of this investigation was to determine the effects of midodrine (10 mg) prescribed TID or BID in the home environment, compared to placebo, on 30-day BP, study withdrawals, and symptom reporting associated with OH and AD in hypotensive individuals with SCI. DESIGN/METHODS: Participants were randomly assigned to received midodrine/placebo or placebo/midodrine, with a 2-weeks washout period in between, and both the participants and investigators were blinded to randomization order. Study medication was taken 2 or 3 times/day, depending on their sleep/wake schedule, BP, and any related symptoms were recorded before and 1 h after each dosage and periodically throughout the day. RESULTS: Nineteen individuals with SCI were recruited; however, 9 withdrew prior to completion of the full protocol. A total of 1892 BP recordings (75 ± 48 recordings/participant/30-day period) were collected in the 19 participants over the two 30-day monitoring periods. Average 30-day systolic BP was significantly increased with midodrine compared to placebo (114 ± 14 vs. 96 ± 11 mmHg, respectively; P = 0.004), and midodrine significantly reduced the number of hypotensive BP recordings compared to placebo (38.7 ± 41.9 vs. 73.3 ± 40.6, respectively; P = 0.01). However, compared to placebo, midodrine increased fluctuations in BP, did not improve symptoms of OH, but did significantly worsen the intensity of symptoms associated with AD (P = 0.03). CONCLUSION: Midodrine (10 mg) administered in the home environment effectively increases BP and reduces the incidence of hypotension; however these beneficial effects come at the expense of worsened BP instability and AD symptom intensity.

No pain, no strain: Targin® mitigates pain and constipation following spinal cord injury.

BACKGROUND: Opioids effectively reduce chronic pain, but present significant side effects including opioid-induced constipation. Oxycodone/naloxone decreases pain and constipation in cancer patients, however its effect on spinal cord injury population remains understudied. METHODS: We assessed whether oxycodone/naloxone reduces pain, constipation, and severity of autonomic dysreflexia in an individual with spinal cord injury. A 55-year-old male with C5 lesion presented with chief complaint of chronic pain received 5/2.5 mg and 20/10 mg oxycodone/naloxone for 6 and 2 weeks, respectively. RESULTS: Oxycodone/naloxone improved pain, bowel function, and autonomic dysreflexia severity. INTERPRETATION: Oxycodone/naloxone was effective in managing chronic pain and constipation in the studied case.

Fesoterodine Ameliorates Autonomic Dysreflexia While Improving Lower Urinary Tract Function and Urinary Incontinence-Related Quality of Life in Individuals With Spinal Cord Injury: A Prospective Phase IIa Study.

The aim of this prospective phase IIa, open-label exploratory, pre-post study was to determine the efficacy of fesoterodine (i.e., 12-week treatment period) to ameliorate autonomic dysreflexia (AD) in individuals with chronic SCI (> 1-year post-injury) at or above the sixth thoracic spinal segment, with confirmed history of AD and neurogenic detrusor overactivity (NDO). Twelve participants (four females, eight males; median age 42 years) completed this study and underwent urodynamics, 24-h ambulatory blood pressure monitoring (ABPM), and urinary incontinence-related quality of life (QoL) measures at baseline and on-treatment. The Montreal Cognitive Assessment (MoCA) and Neurogenic Bowel Dysfunction (NBD) score were used to monitor cognitive and bowel function, respectively. Compared with baseline, fesoterodine improved lower urinary tract (LUT) function, that is, increased cystometric capacity (205 vs. 475 mL, p = 0.002) and decreased maximum detrusor pressure (44 vs. 12 cm H2O, p = 0.009). NDO was eliminated in seven (58%) participants. Severity of AD events during urodynamics (40 vs. 27 mm Hg, p = 0.08) and 24-h ABPM (59 vs. 36 mm Hg, p = 0.05) were both reduced, yielding a large effect size (r = -0.58). AD Frequency (14 vs. 3, p = 0.004) during 24-h ABPM was significantly reduced. Urinary incontinence-related QoL improved (68 vs. 82, p = 0.02), however, cognitive (p = 0.2) and bowel function (p = 0.4) did not change significantly. In conclusion, fesoterodine reduces the magnitude and frequency of AD, while improving LUT function and urinary incontinence-related QoL in individuals with chronic SCI without negatively affecting cognitive or bowel function.

Are local analgesics effective in reducing autonomic dysreflexia in individuals with spinal cord injury? A systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: To systematically review the evidence on the use of local analgesics, specifically lidocaine or bupivacaine, to prevent autonomic dysreflexia (AD) during iatrogenic procedures or bowel and bladder care routines in individuals with spinal cord injury (SCI). METHODS: A keyword search of MEDLINE, CINAHL, CENTRAL, Cochrane Reviews, PsycInfo, Embase, and Web of Science databases identified all English-language studies evaluating the efficacy of local analgesics in reducing AD. Included studies were either randomized controlled trials (RCTs) or quasi-experimental studies. Participants were adults with chronic SCI who received local analgesics prior to AD-triggering procedures or routines. Additionally, studies were required to report blood pressure values as an outcome. The methodology of this review followed the PRISMA checklist and was registered with PROSPERO (CRD42021219506). RESULTS: Four RCTs and two quasi-experimental studies met inclusion criteria. Results were narratively synthesized as meta-analysis was not possible due to heterogeneity across studies included in the review. All six studies administered lidocaine. Lidocaine was found to have a beneficial effect on AD in three studies, no effect in two studies and a detrimental effect in one study. CONCLUSIONS: Presently, RCTs and quasi-experimental studies on the use of lidocaine for reducing AD in individuals with SCI had small sample sizes and opposing findings. There is a strong need for definitive, well-monitored clinical trials with adequate sample sizes. Presently there is not enough compelling evidence to support or refute recommendations for the use of lidocaine from the AD management clinical practice guidelines.

Rectal Application of Lidocaine Reduces the Severity of Autonomic Dysreflexia following Experimental Spinal Cord Injury.

Spinal cord injury (SCI) results in devastating cardiovascular dysfunction. Noxious stimuli from the rectum during bowel routine often trigger life-threatening blood pressure surges, termed autonomic dysreflexia (AD). Rectal application of anesthetic lidocaine jelly has been recommended during bowel care to reduce AD severity by mitigating sensory input. However, clinical studies have reported contradicting evidence. We performed a pre-clinical study on the efficacy of rectal lidocaine in a standardized rodent T3 transection model. We found that 2% and 10% lidocaine significantly reduced AD severity by 32% and 50%, respectively, compared with control (p < 0.0001). Our pre-clinical experiments support the current recommendation of rectal lidocaine application during bowel care.

Management of blood pressure disorders in individuals with spinal cord injury.

Blood pressure regulation is impacted by a spinal cord injury (SCI) due to impaired descending sympathetic vascular control. Common blood pressure problems in the SCI population include persistently low blood pressure with bouts of orthostatic hypotension and autonomic dysreflexia, which are more prevalent in individuals with lesions above the sixth thoracic vertebral level; however, they may occur regardless of the neurological level of injury. Although blood pressure disorders adversely impact daily function and quality of life, most individuals with SCI do not acknowledge this association. Few pharmacological options have been rigorously tested for safety and efficacy to manage blood pressure disorders in the SCI population. Furthermore, clinical management of any one blood pressure disorder may adversely impact others, as such treatment is complicated and not often prioritized.

Medical emergency: rash, headache and spinal cord injury.

A 49-year-old consultant medical oncologist, with a medical history of complete T5 spinal cord injury (March 1992) and long-term paralysis from the chest down, presented with shingles affecting the T7 dermatome. He also had a dull frontal headache, a feeling of agitation and increased blood pressure of 135/90 on a home blood pressure machine (higher than his usual blood pressure of 90/70). Having been taught about autonomic dysreflexia at the time of his initial spinal cord injury, he self-diagnosed autonomic dysreflexia caused by the noxious stimulus of shingles below his level of spinal cord injury. He self-administered a nifedipine 5 mg sublingual capsule to decrease his blood pressure before urgently seeing his general practitioner. Treatment of the shingles with acyclovir and analgesia successfully managed the problem and avoided hospital admission. This case highlights key aspects in treating autonomic dysreflexia and the value of doctor-patient partnership in doing so.

Design and characterisation of an amorphous formulation of nifedipine for the treatment of autonomic dysreflexia.

OBJECTIVES: Current treatment for autonomic dysreflexia (AD) involves rupturing a liquid-filled soft capsule of nifedipine to aid rapid drug release and absorption, however, this application is not covered under the manufacturer's license. The objective of the current work was to design a rapidly dissolving solid dosage formulation for the treatment of AD as an alternative to the off-license "bite and swallow" use of currently available commercial products. METHODS: Amorphous solid dispersions (ASDs) of nifedipine were prepared by spray-drying using three different polymers: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), at a 15% w/w drug loading and were formulated and compressed into tablets. Dissolution testing was performed in the paddle dissolution apparatus using either a monophasic or biphasic medium. KEY FINDINGS: The PVP-nifedipine ASD tablets exhibited rapid dissolution, with 35% of the total nifedipine dose dissolving within 15 min in the monophasic dissolution medium. The HPMC-nifedipine ASD exhibited a very slow dissolution, while the Solupus-nifedipine system exhibited no nifedipine release over 120 min. When tested in the biphasic dissolution medium, the PVP-nifedipine ASD tablets exhibited a release profile comparable to that of the pre-split/ruptured nifedipine soft capsule product. CONCLUSIONS: This study demonstrates that a nifedipine-PVP ASD is a promising formulation strategy in the treatment of AD.

Purinergic receptor antagonism: A viable strategy for the management of autonomic dysreflexia?

The purinergic receptor ligand, ATP, may participate in reflex induced vasoconstriction through sympathetic efferent and sensory afferent mechanisms. However, the role of the purinergic system in contributing to autonomic dysreflexia following spinal cord injury is unclear. The present study investigates the involvement of P2X receptors in contributing to pressor responses during autonomic dysreflexia. Twenty rats were subjected to spinal cord injury and 24 h later hemodynamic responses to colorectal distension were recorded. Animals were randomized to receive intravenous administration of the P2X receptor antagonist, NF023, or vehicle control. The data indicate that NF023 attenuates pressor responses to colorectal distension.

Intrathecal baclofen as emergency treatment alleviates severe intractable autonomic dysreflexia in cervical spinal cord injury.

Context: Episodic attacks of autonomic dysreflexia (AD) are regularly experienced by patients with a spinal cord injury (SCI) on T6 or higher levels. The episodes can result in a pounding headache, flushing, blurred vision, anxiety, a stroke, posturing, hyperthermia, retinal bleeding, seizures, myocardial ischemia, cardiac arrhythmias, and death. The observed associated bradycardia is explained as a baroreceptor reflex response to the high blood pressure. Intrathecal baclofen (ITB) has been used to treat chronic AD. This case highlights the occurrence of intractable AD after removal of the ITB delivery system because of a pump pocket infection. We describe the benefit of ITB as an emergency treatment for intractable AD.Findings: A 53-year-old male suffered from spasticity and AD after a C5 ASI B SCI in 2002 was successfully treated with ITB for 14 years. He developed Staphylococcus aureus and Pseudomonas aeruginosa cellulitis at the orifice of his suprapubic catheter, which caused an abscess in the pump pocket. To prevent a withdrawal syndrome, the medication was reduced in three steps of 25%, and the pump was explanted. Postoperatively, he experienced severe AD and was treated with clonazepam, clonidine, and urapidil. The next day, the severely fluctuating blood pressure and pulse rate were no longer controllable with the medication. At L2-3, a temporary external intrathecal catheter for reinitiating ITB was inserted. With this treatment, the AD and the spasticity symptoms could be controlled.Conclusion/Clinical Relevance: The case demonstrated that refractory AD could be managed with ITB in an emergency.

Discitis following urinary tract infection manifesting as recurrent autonomic dysreflexia related to truncal movements in a person with tetraplegia.

A 44-year-old male person with tetraplegia (C-5 AIS-A (American Spinal Cord Injury Association Standard Neurological Classification of Spinal Cord Injury Impairment Scale)) developed urinary tract infection and received appropriate antibiotic. Subsequently, he started sweating and shivering when he was sitting up; these symptoms resolved while lying on his back. Autonomic dysreflexia triggered by truncal movements continued to occur for 3 months. CT of the spine showed L5-S1 discitis. MRI of the spine showed diffuse marrow oedema in L5 and S1 vertebrae and a large abscess at L5/S1 level. Blood culture yielded Serratia marcescens sensitive to meropenem. Meropenem followed by ertapenem was given for 12 weeks. After 11 months, MRI showed resolution of discitis and epidural collection. The patient was able to sit up for 9 hours without developing autonomic dysreflexia. If a person with cervical spinal cord injury develops posture-related autonomic dysreflexia (eg, in sitting position, lying on sides or while hoisted), disco-vertebral pathology should be suspected.

Autonomic dysreflexia in a case of radiation myelopathy and cisplatin-induced polyneuropathy.

INTRODUCTION: While autonomic dysreflexia caused by severe spinal cord lesions can be life-threatening, relevant reports on non-traumatic spinal lesions are rare. Furthermore, modes of innervation of the supraspinal inhibitory pathways at each spinal sympathetic segment remain unknown. Herein, I report the case of a patient with autonomic dysreflexia and radiation myelopathy. The laterality of autonomic dysreflexia was investigated with special reference to the sudomotor function. CASE PRESENTATION: A 51-year-old man with a history of epipharynx carcinoma, radiotherapy, and cisplatin chemotherapy was referred for the evaluation of autonomic function. He was ambulant but displayed spastic tetraparesis, areflexia of the extremities, sensory disturbance below C4 dermatome, dysuria, and impotence. Spinal magnetic resonance imaging demonstrated a cervical lesion involving the lateral portion of C2-C5, bilaterally. The thermal sweating test showed that sweating was lower on the left side of the face and neck, left shoulder, and arm than the corresponding parts on the right side. The rest of the body was anhidrotic. Sweating due to autonomic dysreflexia was symmetric, but more abundant on the left side of the face. Acetylcholine-induced sweating was markedly reduced on the left leg. DISCUSSION: This might be the first documentation of autonomic dysreflexia observed in a patient with radiation myelopathy. The present observations suggested that the supraspinal inhibitory pathway to spinal preganglionic neurons may descend on the same side as thermal sudomotor facilitatory pathways at the cervical level. Furthermore, autonomic dysreflexia was more prominent in the standing position suggesting that the pressure stimulus might enhance autonomic dysreflexia.

Intradetrusor OnabotulinumtoxinA Injections Ameliorate Autonomic Dysreflexia while Improving Lower Urinary Tract Function and Urinary Incontinence-Related Quality of Life in Individuals with Cervical and Upper Thoracic Spinal Cord Injury.

Pilot data of our phase IV clinical trial (pre/post study design) highlighted a beneficial effect of intradetrusor onabotulinumtoxinA (200 IU) injections to reduce autonomic dysreflexia (AD) in individuals with chronic spinal cord injury (SCI) at T6 or above. After trial completion, we assessed whether our primary expectation (i.e., decrease of AD severity in 50% of participants during urodynamics [UDS]) was met. Secondary outcome measures were reduction of spontaneous AD in daily life as well as amelioration of AD-related and urinary incontinence-related quality of life (QoL). In addition, we conducted injury-level-dependent analysis-i.e., cervical and upper thoracic-to explore group-specific treatment efficacy. Post-treatment, AD severity decreased in 82% (28/34) of all participants during UDS and in 74% (25/34) in daily life assessed with 24-h ambulatory blood pressure monitoring. In addition, urinary incontinence-related QoL was improved, cystometric capacity was increased, and maximum detrusor pressure during storage was reduced (all p < 0.001). Further, the treatment was well tolerated, with only minor complications (grade I [n = 7] and II [n = 7]) in accordance with the Clavien-Dindo classification recorded in 11 individuals (cervical n = 9, upper thoracic n = 2). Injury-level-dependent analysis revealed lower incidence (cervical n = 15/23, upper thoracic n = 6/11) and lesser severity (cervical p = 0.009; upper thoracic p = 0.06 [Pearson r = -0.6, i.e., large effect size]) of AD during UDS. Further, reduced AD severity in daily life, improved urinary incontinence-related QoL, greater cystometric capacity, and lower maximum detrusor pressure during storage (all p < 0.05) were found in both groups post-treatment. Intradetrusor onabotulinumtoxinA injections are an effective and safe second-line treatment option that ameliorates AD while improving lower urinary tract function and urinary incontinence-related QoL in individuals with cervical and upper thoracic SCI.

Effect of intravesical botulinum toxin injection on symptoms of autonomic dysreflexia in a patient with chronic spinal cord injury: a case report.

Context: There are few treatment options for managing autonomic dysreflexia in patients with chronic spinal cord injury (SCI). According to some studies, intravesical botulinum toxin for SCI patients with autonomic dysreflexia has a preventive effect on symptoms of autonomic dysreflexia. However, the usefulness of an intravesical botulinum toxin injection has never been reported for autonomic dysreflexia in an adult patient with chronic cervical SCI, although there has been for one pediatric patient.Findings: A 62-year-old man with chronic cervical SCI had neurogenic bladder due to C6-7 SCI since sustaining a fall in 1980. He presented with an intermittent headache and severe hypertension because of persistent autonomic dysreflexia. His symptoms did not improve with conservative management, and he could not undergo an operation to resect the lung cancer because of his uncontrolled blood pressure. To control his fluctuating blood pressure, he was taken to an operating room to receive an intravesical botulinum toxin injection for refractory bladder spasms. Subsequently, his blood pressure was controlled, and then the lung mass could be surgically removed. His improved condition lasted for more than 6 months.Conclusion: This case suggests that botulinum toxin is a logical treatment option for autonomic dysreflexia as well as neurogenic detrusor overactivity in patients with chronic SCI. Dedicated research is warranted to assess the efficacy of an intravesical botulinum toxin injection, as it was used successfully to stop the symptoms of autonomic dysreflexia in our patient.

Protocol for a phase II, open-label exploratory study investigating the efficacy of fesoterodine for treatment of adult patients with spinal cord injury suffering from neurogenic detrusor overactivity for amelioration of autonomic dysreflexia.

INTRODUCTION: Managing and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals. However, individuals with spinal cord injury (SCI) at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from neurogenic detrusor overactivity (NDO). Treatment of NDO would not only improve lower urinary tract function but could also reduce the severity and frequency of life-threatening episodes of AD. Fesoterodine, an antimuscarinic drug, has been successfully employed as a first-line treatment for detrusor overactivity in individuals without an underlying neurological disorder. Thus, our aim is to investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI. METHODS AND ANALYSIS: This phase II, open-label exploratory, non-blinded, non-randomised, single-centre study will investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6. During screening, we will interview potential candidates (with a previous history of NDO and AD) and assess their injury severity. At baseline, we will perform cardiovascular and cerebrovascular monitoring (blood pressure (BP), heart rate and cerebral blood flow velocity) during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to assess severity and frequency of AD episodes (ie, maximum increase in systolic BP). The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy. To answer this, we will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, ie, three cycles of 4 weeks each). At the end of each treatment cycle, participants will be asked to answer standardised questionnaires (AD symptoms and quality of life) and present bladder and bowel diaries, which will provide additional subjective information. ETHICS AND DISSEMINATION: The University of British Columbia Research Ethics Boards (H15-02364), Vancouver Coastal Health Research Institute (V15-02364) and Health Canada (205857) approved this study. The findings of the study will be published in peer-reviewed journals and presented at national and international scientific meetings. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials and CONsolidated Standards Of Reporting Trials statements. TRIAL REGISTRATION NUMBER: NCT02676154; Pre-results.

Changes in sympathetic neurovascular function following spinal cord injury.

The effects of spinal cord injury (SCI) on sympathetic neurovascular transmission have generally been ignored. This review describes changes in sympathetic nerve-mediated activation of arterial vessels to which ongoing sympathetic activity has been reduced or silenced following spinal cord transection in rats. In all vessels studied in rats, SCI markedly enhanced their contractile responses to nerve activity. However, the mechanisms that augment neurovascular transmission differ between the rat tail artery and mesenteric artery. In tail artery, the enhancement of neurovascular transmission cannot be attributed to changes in sensitivity of the vascular muscle to α1- or α2-adrenoceptor agonists. Instead the contribution of L-type Ca2+ channels to activation of the smooth muscle by nerve-released noradrenaline is greatly increased following SCI. By contrast, mesenteric arteries from SCI rats had increased sensitivity to phenylephrine but not to methoxamine. While both phenylephrine and methoxamine are α1-adrenoceptor agonists, only phenylephrine is a substrate for the neuronal noradrenaline transporter. Therefore the selective increase in sensitivity to phenylephrine suggests that the activity of the neuronal noradrenaline transporter is reduced. While present evidence suggests that sympathetic vasoconstrictor neurons do not contribute to the normal regulation of peripheral resistance below a complete SCI in humans, the available evidence does indicate that these experimental findings in animals are likely to apply after SCI in humans and contribute to autonomic dysreflexia.