Pharmacodynamics and effectiveness of topical nitroglycerin at lowering blood pressure during autonomic dysreflexia.

STUDY DESIGN: Secondary analysis of prospectively collected observational data assessing the safety of an autonomic dysreflexia (AD) management protocol. OBJECTIVES: To estimate the time to onset of action, time to full clinical effect (sustained systolic blood pressure (SBP) <160 mm Hg) and effectiveness of nitroglycerin ointment at lowering blood pressure for patients with spinal cord injuries experiencing AD. SETTING: US Veterans Affairs inpatient spinal cord injury (SCI) unit. METHODS: Episodes of AD recalcitrant to nonpharmacologic interventions that were given one to two inches of 2% topical nitroglycerin ointment were recorded. Pharmacodynamics as above and predictive characteristics (through a mixed multivariate logistic regression model) were calculated. RESULTS: A total of 260 episodes of pharmacologically managed AD were recorded in 56 individuals. Time to onset of action for nitroglycerin ointment was 9-11 min. Time to full clinical effect was 14-20 min. Topical nitroglycerin controlled SBP <160 mm Hg in 77.3% of pharmacologically treated AD episodes with the remainder requiring additional antihypertensive medications. A multivariate logistic regression model was unable to identify statistically significant factors to predict which patients would respond to nitroglycerin ointment (odds ratios 95% confidence intervals 0.29-4.93). The adverse event rate, entirely attributed to hypotension, was 3.6% with seven of the eight events resolving with close observation alone and one episode requiring normal saline. CONCLUSIONS: Nitroglycerin ointment has a rapid onset of action and time to full clinical effect with high efficacy and relatively low adverse event rate for patients with SCI experiencing AD.

Suppression and recovery of spermatogenesis following spinal cord injury in the rat.

Recently, we reported that changes in spermatogenesis in adult rats during acute phase (within 2 weeks) of spinal cord injury (SCI) were associated with a suppression of pituitary-testis hormone axis, and these effects mimic those that occur after hormone deprivation. In this study, we examined the long-term (>4 weeks) effects of SCI on spermatogenesis and its recovery. Results of this study reveal that while serum follicle stimulating hormone, luteinizing hormone, and testosterone levels in SCI rats recovered within 1 month after the injury, their spermatogenesis continued to regress. By 3 months, spermatogenesis in 70% of SCI rats has totally regressed, characterized by the absence of proliferating spermatogonia; these effects could not be prevented by an otherwise effective regimen of testosterone treatment. Sertoli cells in the regressed seminiferous tubules exhibited unusual behavior, characterized by the formation of multiple cell layers and/or aggregates that extended into the tubular lumen. Active spermatogenesis was observed in nine of the 19 SCI rats by 6 months, seven of which had complete spermatogenesis, but with persisting abnormalities. These results demonstrate that SCI results in total, but reversible, regression of spermatogenesis. Failure to prevent such effects by an otherwise effective exogenous testosterone regimen suggests that non-endocrine factors are involved in the SCI effects on spermatogenesis. The unusual Sertoli cell localization in the regressed testes may have been triggered by the loss of proliferating spermatogonia and may be involved in subsequent spermatogenic recovery.

The effects of spinal cord injury on the status of messenger ribonucleic acid for TRPM 2 and androgen receptor in the prostate of the rat.

The prostate is one of the male accessory sex glands that produce fluid components of the seminal plasma. In addition to androgen, a normal innervation of the prostate is believed to be important for maintaining normal function of the prostate. Previously we noted that, in the rat, the weight of the prostate decreased following surgically induced spinal cord injury (SCI). This observation suggests that growth, and possibly function, of the prostate may be compromised after SCI. To explore this possibility, we examined the effects of SCI on the androgen-related biochemical properties and morphology of the prostate in the rat at various times after surgically induced SCI. SCI resulted in an acute decrease in prostate weight and an increase in steady state level of mRNA for testosterone-repressed prostate message 2 (TRPM 2) during the first 2 weeks postinjury. These changes perhaps relate to an increase in cell death or a decrease in secretory activity due to an acute suppression of serum testosterone after the injury. Concomitantly, there was a transient, but significant, decrease in the steady state level of androgen receptor (AR) mRNA in the prostate during the first 2 weeks after SCI, an indication of an altered autoregulation of AR by its own ligand. Despite the fact that growth of the prostate, as indicated by weight increase, in SCI rats resumed 2 weeks postinjury, prostate weights were persistently lower in SCI rats than sham-operated controls for at least 3 months. Furthermore, prostate TRPM 2 mRNA levels remained elevated throughout the recovery period even after a normal prostate weight had been restored. In addition, a decrease in the height of ventral prostate epithelial cells was noted in SCI rats 28 and 90 days postinjury. These results demonstrate a prolonged effect of SCI on prostate function. These findings and our unreported observation of persistently smaller seminal vesicles in the same groups of SCI rats suggest that functions of male accessory sex glands may also be compromised after SCI. These changes may affect biochemical properties of the secretory products of these glands and may provide some explanation for the reported changes in the composition of the seminal plasma and abnormal sperm motility seen in the semen of SCI men.

Acute effects of spinal cord injury on the pituitary-testicular hormone axis and Sertoli cell functions: a time course study.

The present study investigated the time course of the onset of the abnormalities in spermatogenesis following spinal cord injury, and their relationship to changes in the pituitary testicular hormonal axis and Sertoli cell function. Spinal cord injury (SCI) was induced in adult male rats by surgical transection of the spinal cord at the level of T9 and L1 vertebrae. Animals were killed 3, 7, and 14 days after the operation. As early as 3 days following SCI, abnormalities in spermatogenesis, including delayed spermiation and vacuolization of the nucleus of spermatids, were noted in both the T9 and L1 animals. By 14 days, other lesions, including phagocytosis of mature spermatids, incomplete cellular associations, and total regression of seminiferous epithelium, became apparent. Concurrently a transient but significant (P < 0.05) suppression of serum follicle-stimulating hormone (FSH) occurred in the T9 animals, and a suppression of serum luteinizing hormone (LH) occurred in both the T9 and the L1 animals 3 days after the surgery. This was accompanied by a suppression of testicular and serum testosterone levels (P < 0.05, P < 0.01, respectively). Most of the hormonal parameters had recovered and were not different from those of sham-operated animals by 14 days (P > 0.10). Northern blot analysis of testicular poly(A)+ RNA revealed a transient but significant reduction in the steady-state level of the 2.7-kilobase (kb) Sertoli cell transferrin mRNA transcript in both the T9 and the L1 animals 3 days after the operation (P < 0.05). On the other hand, the 1.7-kb androgen binding protein (ABP) mRNA remained unaffected during the 2-week study period. The steady-state level of mRNA transcripts for spermatogenic cell-specific hemiferrin and spermatid specific transition protein 2 and protamine 1 also remained unchanged. These results suggest that spinal cord injury will result in a temporary, but profound, effect on the pituitary-testicular hormone axis. These changes may impair certain aspects of Sertoli cell function that could render these cells incapable of supporting normal spermatogenesis. However, the severity of spermatogenic lesions and the disparate responses of the two major Sertoli cell proteins make it unlikely that hormone deficiency is the only mechanism responsible for the impaired spermatogenesis following spinal cord injury.

Prevalence of urinary incontinence after brain injury.

There is little reported in the literature describing the prevalence of voiding dysfunction after brain injury. A prospective study was conducted, 54 consecutive admissions to our brain injury unit from September 1992 through January 1993 were screened for signs and symptoms of voiding dysfunction. Signs and symptoms were noted in 24 patients (44.4%). There was no statistically significant difference in symptom prevalence based on age, sex, hemisphere (right or left) injured, or presence or absence of a frontal lobe injury. Those functioning at a lower cognitive level (Rancho Los Amigos Scale VI or less) had a higher symptom prevalence than the VII-VIII group (p = 0.004, Chi Square Test).

Voiding Symptoms and Bladder Function Following CVA: A Prospective Time Course Study.

This is the first prospective study evaluating both urinary complaints and bladder physiology following acute cerebrovascular accidents (CVAs). Consecutive patients with acute CVAs were entered into this study. Voiding histories and urodynamics were performed 1-2 weeks post-CVA, 1-2 months post-CVA, 4-10 months post-CVA, and 5 months later (9-15 months post-CVA). Previous studies have focused on urinary incontinence and reported that this problem resolves in the majority of patients. This study also found that urinary incontinence resolved. However, other urinary complaints, such as urinary frequency and nocturia, which also had a significant adverse impact on the individuals' lifestyle, continued to persist. Urodynamic studies at one year revealed that uninhibited bladder contractions persisted despite resolution of incontinence. There was no obvious relationship between the location of the CVA in the right hemisphere and those who did or did not develop urologic symptoms.

A method to minimize indwelling catheter calcification and bladder stones in individuals with spinal cord injury.

Indwelling catheters are a common tool of bladder management in persons with high-level spinal cord injury who are unable to intermittently catheterize their bladders. Indwelling catheters are used to prevent bladder overdistension, which can trigger autonomic dysreflexia in those with injuries at or above T6. Unfortunately, indwelling catheters are prone to encrustation and can lead to the formation of bladder stones that can block the catheter and cause autonomic dysreflexia. We found that weekly catheter changes dramatically reduced catheter encrustation and stones in 2 individuals who had a history of recurrent stones despite various accepted interventions. We describe the clinical course and impact of this method in each case.

Effectiveness of neomycin/polymyxin bladder irrigation to treat resistant urinary pathogens in those with spinal cord injury.

Individuals with spinal cord injury (SCI) will sometimes develop bacterial organisms in the bladder that are resistant to oral antibiotics. This study evaluated the effectiveness of a 5-day course of intermittent neomycin/polymyxin bladder irrigation at eradicating or changing the bacterial sensitivity from parenteral to oral antibiotics. A chart review of individuals with SCI who were treated with neomycin/polymyxin bladder irrigations was performed. Inclusion criteria included the use of an indwelling catheter and the presence of asymptomatic bacteria resistant to oral antibiotics. The most common reason for treatment was eradication of resistant organisms prior to urologic testing. Bladder irrigation consisted of 3 rinses with 30 ml 3 times a day for 5 days. Pre- and post-urine samples were compared for white blood cells (WBCs), colony count and culture, and sensitivity. Chi-square tests were used to determine whether the proportion of changes in resistance or sensitivities was different from zero. The Wilcoxon Signed Rank Test was used to determine differences in bacteria, colony counts, and WBCs. Ten individuals were identified. A total of 12 neomycin/polymyxin irrigation treatments were evaluated because 2 individuals had a second series of irrigations at least 6 months apart. Nine of the 12 (75%) were considered to have successful irrigations because there was a change in culture sensitivity so that oral antibiotics would be effective post irrigation. This was statistically significant. There were no significant changes in colony counts or the number of WBCs. The authors concluded that while neomycin/polymyxin bladder irrigation did not change the type of organism, it was effective in changing resistance of most organisms. Individuals could then be treated with oral rather than intravenous or intramuscular antibiotics. Further work is needed to determine whether other variables, such as increased length of time of irrigation or increased frequency of irrigations, may actually eradicate the organisms.

The impact of urodynamic parameters on the upper tracts of spinal cord injured men who void reflexly.

Few studies have evaluated which urodynamic parameters impact the upper urinary tracts in men with complete spinal cord injuries (SCI) who void reflexly. Previous studies focused primarily on voiding pressures. This study investigated the effects of bladder wall compliance, opening pressure, maximum detrusor voiding pressure, duration of the uninhibited contraction, cystometric bladder capacity and post-void residual on vesicoureteral reflux and stasis of the upper tracts. Urodynamic studies, cystograms and renal scans of 84 consecutive men with complete SCI who void reflexly were evaluated. Of the 84 patients (168 renal units), 71 men (142 renal units) had normal upper tracts, four patients (four renal units) had vesicoureteral reflux and nine patients (15 renal units--12 bilateral, three unilateral) had upper urinary tract stasis. There was no statistical difference between those with reflux and those without reflux with regards to any urodynamic parameter evaluated. When comparing those with and without upper urinary tract stasis, the only statistically significant difference in urodynamic parameters was the duration of bladder contraction. The mean duration of the uninhibited contraction in the non-stasis group was 113.7 seconds +/- 84 seconds (1.9 minutes +/- 1.4 minutes). The mean duration of the uninhibited contraction in the stasis group was 236.4 seconds +/- 139.1 seconds (3.9 minutes +/- 2.3 minutes, p = 0.0098). In summary, the duration of bladder contraction, which reflects both detrusor and sphincter function, was found to be an important variable in those with upper tract stasis. This should be considered when evaluating and treating men with complete SCI who void reflexly.

Mechanical properties of bone in a paraplegic rat model.

Pathologic fractures may occur with minimal trauma after spinal cord injury (SCI) because of osteoporosis. Rats were evaluated to determine whether they could be used as an SCI animal model. Male Sprague-Dawley rats underwent spinal cord transection at the ninth thoracic vertebrae. Control rats underwent a sham procedure. Mechanical testing of the humeral shaft, femoral shaft, tibial shaft, femoral neck, distal femur, and proximal tibia was performed separately at 0, 8, and 24 weeks after surgery. At 24 weeks, significant differences between SCI and control rats were found in maximum torque needed to produce failure in the femoral shaft (63 percent of control, p < 0.05) and tibial shaft (63 percent, p < 0.01), and in compressive load to produce failure in cross-sectional specimens of the distal femur (51 percent, p < 0.05) and proximal tibia (50 percent, p < 0.01). No differences were found in the maximum torque needed to produce failure of the humeral shaft (106 percent, p = 0.77) between SCI and control rats. Reductions in relative bone strength in SCI rats at 24 weeks were similar in magnitude to bone mineral density changes reported in humans with chronic paraplegia. Thus, Sprague-Dawley rats appear to be good animal models in which to evaluate changes in bone strength following SCI.

Effects of the routine change of chronic indwelling Foley catheters in persons with spinal cord injury.

OBJECTIVE: To determine whether routine catheter changes have any effect on the urinary white blood cell count (WBC) and bacterial culture in asymptomatic individuals with spinal cord injury (SCI) who have indwelling Foley catheters. DESIGN: Prospective case series. SETTING: Urology and SCI outpatient departments of a rehabilitation center. SUBJECTS: Twelve asymptomatic individuals (male and female) with SCI who have chronic indwelling urethral Foley catheters that are changed routinely every month. MAIN OUTCOME MEASURES: Two sets of urinalysis and urinary culture and sensitivity from each individual, one set taken through the Foley catheter before the catheter change and another set after the catheter change. WBC, bacterial identity, and colony count were measured, and the corresponding data were compared. RESULTS: All subjects had pyuria and bacteriuria before and after the catheter change. Analysis of the data showed a statistically significant increase in WBC in the urine after the indwelling Foley catheter was changed (P = .0039). However, bacterial types and corresponding colony counts remained almost completely unchanged. CONCLUSIONS: Routine change of chronic indwelling Foley catheters in asymptomatic individuals with SCI causes a significant rise in the urinary WBC, without altering the bacterial identity or colony count. Pyuria and bacteriuria are prevalent among individuals with SCI (including those who are asymptomatic) with indwelling Foley catheters. This study suggests that urinalysis should be taken before a catheter change.

The reproducibility of urodynamic studies of neurogenic bladders in spinal cord injury.

OBJECTIVE: To evaluate the reproducibility (test-retest reliability) of urodynamic studies in neurogenic bladders of subjects with spinal cord injuries (SCI). DESIGN: Retrospective case series. SETTING: Urology department of a major rehabilitation center. SUBJECTS: Fifty individuals with SCI who had urodynamic studies performed from February 2000 to April 2000. MAIN OUTCOME MEASURES: Two trials (Time 1 and Time 2) of urodynamic studies done 5 minutes apart, with the following collected: bladder volume at first sensation, maximum cystometric capacity, presence of uninhibited contractions, opening pressure, maximum detrusor pressure, duration of bladder contraction, volume voided, and post-void residual (PVR) volume. The corresponding data were then compared. Statistical analysis was performed using the Lin's concordance correlation coefficient and kappa. RESULTS: Analysis of the data showed statistically significant levels of agreement between Time 1 and Time 2 with regard to the various corresponding parameters for both the filling and voiding phases. For 3 of the most important parameters-the opening pressure, maximum detrusor pressure, and duration of contraction-the Lin's concordance correlation coefficient (r(c)) was .86 (95% CI, .78-.95; p < .0005), .91 (95% CI, .86-.96; p < .0005), and .97 (95% CI, .95-.99, p < .0005), respectively. CONCLUSION: The study demonstrates good short-term intrasubject reproducibility of urodynamic studies in individuals with SCI.

Epididymal sperm transport in normal and recent spinal cord injured Sprague Dawley rats.

Causes of poor semen quality following spinal cord injury (SCI) are not known. One possible reason, based upon studies that reported improved semen quality in SCI men after several induced ejaculations, is delayed epididymal sperm transport. Our study was designed to establish baseline epididymal sperm transport values in the Sprague Dawley rat and evaluate effects of SCI on this process. Spermatozoa protamine was labeled with tritiated arginine, and the rats were sacrificed various times after injection. Each epididymis was divided into six equal sections from proximal to distal. Sperm tails were dissolved with 8 molar (M) urea in the presence of 2 mM dithiothreitol (DTT); sperm heads were collected by centrifugation (3,000 rpms, 10 min.). The radioactivity in sperm heads from each section was counted and expressed as counts per million sperm heads. To account for different rates of labeled arginine incorporation, the percentage of counts per million sperm heads in each section was calculated relative to the total number of counts in all six sections. Our results showed there was an orderly progression of sperm through the epididymis. It took 8 days for labeled sperm to enter the epididymis and 28 days to peak in the caudal (tail) section in non-SCI rats. Stasis was present 10 days after T-9 SCI in rats compared with transport in sham controls. This was evidenced by a significant increase in the percentage of labeled sperm in proximal sections of the epididymis (sections 1, 2, and 4) in T-9 transected animals (p < 0.01). If similar stasis occurs in SCI men, it could obviously contribute to poor semen quality. However, it remains to be determined how long this stasis persists after SCI in rats.

Does refrigeration of urine alter culture results in hospitalized patients with neurogenic bladders?

A prospective, blinded study of 40 hospitalized spinal cord injured (SCI) patients was conducted to evaluate the effects of refrigeration on urinalysis and culture results. Urine samples were divided, with one aliquot examined within 4 hours and the other after 24 hours of refrigeration. Comparisons using Wilcoxon Signed Rank analysis showed no significant difference between fresh and refrigerated samples in white blood cell (WBC) count (z = -0.353, p = 0.724), number of bacteria (z = -0.772, p = 0.440), leukocytes (z = -0.277, p = 0.782), or colony counts of E. fecalis, E. coli, Citrobacter, Pseudomonas, Streptococcus, Yeast, or Acinetobacter (z = -1.00, p = 0.317; z = 0.00, p = 1.0; z = 0.00, p = 1.0; z = 0.00, p = 1.0; z = -1.00, p = 0.317; z = 0.00, p = 1.0; z = 0.00, p = 1.0, respectively). A statistically significant difference between fresh and refrigerated samples was found with "mixed" organisms (z = -2.565, p = 0.010) and a difference approaching significance was found with Staph aureus (z = -1.841, p = 0.066), both with colony counts of less than 50 k. No changes in cultures or colony counts occurred following refrigeration that would have resulted in altered treatment regimens. This study indicates that refrigeration of urine samples for up to 24 hours in the hospital setting rarely causes changes in identified organism type and causes no clinically significant changes in urinalysis or urine culture results in SCI patients.

Testicular blood flow following spinal cord injury in the Sprague Dawley rat.

The causes of poor semen quality following spinal cord injury (SCI) are unknown. One possible mechanism is decreased testicular blood flow. Chronic testicular ischemia in non-SCI animals has been shown to have significant adverse impact on spermatogenesis. This study was designed to evaluate testicular blood flow following SCI in the Sprague Dawley rat. Testicular blood flows were determined in 11 rats with SCI at thoracic level nine (T9) and six sham control rats three days prior and three days and 14 days after SCI. Testicular blood flow velocity was measured with a Doppler flow probe. Blood flows were compared between groups using T-tests. There were no significant changes in blood flow in the sham operated rats three or 14 days after surgery. However, three days after SCI, blood flow had decreased in the SCI rats to 78 +/- 5 percent of the pre-SCI flow (t = -4.65 with 10 df, p < 0.001). At 14 days after SCI, blood flow was still decreased to 77 +/- 8 percent, (t = -3.40 with 3 df, p < 0.05). This study established that following SCI, testicular blood flow decreases in the Sprague Dawley rat.

Epidemiology of current treatment for sexual dysfunction in spinal cord injured men in the USA model spinal cord injury centers.

This study is a prospective multicenter cooperative survey of the evaluation and treatment of erectile dysfunction in men with spinal cord injury (SCI). Uniform database questionnaires were completed prospectively by patients seeking therapy for erectile dysfunction. Eighty-five SCI men aged 17-68 years (mean age = 26 +/- 17) were enrolled. Mean duration of traumatic SCI was 3 +/- 3.2 years (Range = 0.3-18 years). The level of injury was cervical in 20 patients, thoracic in 31, lumbar in 29 and sacral in five. Patients were fully evaluated and then counseled as to their therapeutic options. Twenty-eight chose to use a vacuum erection device (VED), 26 preferred pharmacological penile injection and five used both intracorporeal therapy and VED. The remainder were managed with marriage and sexual counseling in 10 patients, three underwent penile prosthesis placement and two used topical pharmacotherapy. Four patients used other forms of treatment and in nine no therapy was recommended. Of the patients that used pharmacologic injection only, 74 percent used papaverine as a single agent, 20 percent used papaverine with phentolamine, five percent used prostaglandin E (PGE1) alone and one percent used a mixture. Patients using injection therapy report sexual intercourse a mean of 3 +/- 3.4 times per month as compared with 5 +/- 3.2 times per month in those using VED. Five intracorporeal injection patients developed priapism while two patients using the VED developed subcutaneous bleeding and one developed penile ischemia. We conclude that although a spectrum of erectile dysfunction treatment is present among SCI centers, VED and pharmacological penile injection are by far the two most popular methods of treatment and papaverine is the most common drug. The incidence of complications is small in the model centers.

Sexual function and infertility following spinal cord injury.

Changes in sexual function and fertility frequently occur following spinal cord injury (SCI). This article presents an overview of human sexual response and the changes that occur in that response following SCI. This article addresses the issues of childbearing for women with SCI, erectile function for men with SCI, and the issues of fertility and parenting for men and women with SCI.

Male infertility following spinal cord injury.

Ejaculatory dysfunction and poor semen quality are responsible for male infertility following spinal cord injury (SCI). Techniques which have been used to obtain semen include intrathecal neostigmine, subcutaneous physostigmine, direct aspiration of sperm from the vas deferens, vibratory stimulation and electroejaculation. Vibratory stimulation and electroejaculation are most widely used in the United States and have a 50-90% success rate at obtaining semen. Poor semen quality following SCI has been attributed to stasis of semen, testicular hyperthermia, urinary tract infections, sperm contact with urine, possible changes in the hypothalamic-pituitary axis, chronic use of various medications and possible sperm antibodies. The outlook for having a child following SCI continues to improve with advancements in obtaining and processing sperm and assisted reproductive technologies.

Evaluation and treatment of erectile dysfunction following spinal cord injury: a review.

The majority of spinal cord injured (SCI) men with upper motor neuron lesions have reflex erections. However, these erections are often not adequately sustained making it difficult if not impossible to have intercourse. The majority of SCI men with lower motor neuron lesions do not have erections. Penile implants are effective in producing erections following SCI. However, they have the disadvantages of being a surgical procedure and of having the risk of infections and erosion of the implant through the skin. Intracavernous injections of papaverine and phentolamine and vacuum erection devices have recently been added to our armamentarium of ways to treat erectile dysfunction. A major concern particularly in SCI men is that papaverine and phentolamine may cause prolonged erections in SCI men. We presently have little data on the use of vacuum devices in SCI men, but preliminary reports on those who are using FDA-approved devices appear promising.