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.

Risk factors for community-associated multidrug-resistant Pseudomonas aeruginosa in veterans with spinal cord injury and disorder: a retrospective cohort study.

STUDY DESIGN: Retrospective cohort studyObjectives:To identify independent risk factors associated with community-associated multidrug-resistant Psedomonas aeruginosa (MDRPA) in a population of veterans with spinal cord injury and disorders (SCI/D). SETTING: A total of 127 Veterans Affairs healthcare facilities. METHODS: Laboratory results from 1 January 2012 to 31 December 2013 were collected, and MDRPA cultures were compared with non-MDRPA cultures. RESULTS: One thousand four hundred forty-one cultures were collected from Veterans with SCI/D, including 227 cultures with MDRPA isolates. Characteristics associated with an increased odds of MDRPA include age 50-64 (adjusted odds ratio (aOR)=1.80, 95% confidence interval (CI)=1.13-2.87), MDRPA culture in the past 365 days (aOR=9.12, 95% CI=5.88-14.15) and carbapenem exposure in the past 90 days (aOR=2.56, 95% CI=1.35-4.87). In contrast, paraplegia was associated with a 53% decreased odds of MDRPA compared with those with tetraplegia (aOR=0.47, 95% CI=0.32-0.69). CONCLUSIONS: Risk factors for community-associated MDRPA include prior history of MDRPA and exposure to carbapenems. Awareness of these factors is important for targeted prevention and treatment of MDRPA in patients with SCI/D.

Risk factors for osteoporotic fractures in persons with spinal cord injuries and disorders.

UNLABELLED: Clinical risk factors for fracture were explored among Veterans with a spinal cord injury. At the end of 11 years of follow-up, the absolute risk of fracture was approximately 20 %. Among the clinical and SCI-related factors explored, a prior history of fracture was strongly associated with incident fracture. INTRODUCTION: Few studies to date have comprehensively addressed clinical risk factors for fracture in persons with spinal cord injury (SCI). The purpose of this study was to identify risk factors for incident osteoporotic fractures in persons with a SCI that can be easily determined at the point of care. METHODS: The Veteran's Affairs Spinal Cord Dysfunction Registry, a national database of persons with a SCI, was used to examine clinical and SCI-related risk factors for fracture. Incident fractures were identified in a cohort of persons with chronic SCI, defined as SCI present for at least 2 years. Cox regression models were used to estimate the risk of incident fractures. RESULTS: There were 22,516 persons with chronic SCI included in the cohort with 3365 incident fractures. The mean observational follow-up time for the overall sample was 6.2 years (median 6.0, IQR 2.9-11.0). The mean observational follow-up time for the fracture group was 3.9 years (median 3.3, IQR 1.4-6.1) and 6.7 years (median 6.7, IQR 3.1-11.0) for the nonfracture group. By the end of the study, which included predominantly older Veterans with a SCI observed for a relatively short period of time, the absolute (i.e., cumulative hazard) for incident fractures was 0.17 (95%CI 0.14-0.21). In multivariable analysis, factors associated with an increased risk of fracture included White race, traumatic etiology of SCI, paraplegia, complete extent of SCI, longer duration of SCI, use of anticonvulsants and opioids, prevalent fractures, and higher Charlson Comorbidity Indices. Women aged 50 and older were also at higher risk of sustaining an incident fracture at any time during the 11-year follow-up period. CONCLUSIONS: There are multiple clinical and SCI-related risk factors which can be used to predict fracture in persons with a SCI. Clinicians should be particularly concerned about incident fracture risk in persons with a SCI who have had a previous fracture.

Development and validation of a computerized algorithm for International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI).

STUDY DESIGN: Validation study. OBJECTIVES: To describe the development and validation of a computerized application of the international standards for neurological classification of spinal cord injury (ISNCSCI). SETTING: Data from acute and rehabilitation care. METHODS: The Rick Hansen Institute-ISNCSCI Algorithm (RHI-ISNCSCI Algorithm) was developed based on the 2011 version of the ISNCSCI and the 2013 version of the worksheet. International experts developed the design and logic with a focus on usability and features to standardize the correct classification of challenging cases. A five-phased process was used to develop and validate the algorithm. Discrepancies between the clinician-derived and algorithm-calculated results were reconciled. RESULTS: Phase one of the validation used 48 cases to develop the logic. Phase three used these and 15 additional cases for further logic development to classify cases with 'Not testable' values. For logic testing in phases two and four, 351 and 1998 cases from the Rick Hansen SCI Registry (RHSCIR), respectively, were used. Of 23 and 286 discrepant cases identified in phases two and four, 2 and 6 cases resulted in changes to the algorithm. Cross-validation of the algorithm in phase five using 108 new RHSCIR cases did not identify the need for any further changes, as all discrepancies were due to clinician errors. The web-based application and the algorithm code are freely available at www.isncscialgorithm.com. CONCLUSION: The RHI-ISNCSCI Algorithm provides a standardized method to accurately derive the level and severity of SCI from the raw data of the ISNCSCI examination. The web interface assists in maximizing usability while minimizing the impact of human error in classifying SCI. SPONSORSHIP: This study is sponsored by the Rick Hansen Institute and supported by funding from Health Canada and Western Economic Diversification Canada.

Surgical compared with nonsurgical management of fractures in male veterans with chronic spinal cord injury.

STUDY DESIGN: Retrospective review of a clinical database. OBJECTIVES: To examine treatment modalities of incident appendicular fractures in men with chronic SCI and mortality outcomes by treatment modality. SETTING: United States Veterans Health Administration Healthcare System. METHODS: This was an observational study of 1979 incident fractures that occurred over 6 years among 12 162 male veterans with traumatic SCI of at least 2 years duration from the Veterans Health Administration (VA) Spinal Cord Dysfunction Registry. Treatment modalities were classified as surgical or nonsurgical treatment. Mortality outcomes at 1 year following the incident fracture were determined by treatment modality. RESULTS: A total of 1281 male veterans with 1979 incident fractures met inclusion criteria for the study. These fractures included 345 (17.4%) upper-extremity fractures and 1634 (82.6%) lower-extremity fractures. A minority of patients (9.4%) were treated with surgery. Amputations and disarticulations accounted for 19.7% of all surgeries (1.3% of all fractures), and the majority of these were done more than 6 weeks following the incident fracture. There were no significant differences in mortality among men with fractures treated surgically compared with those treated nonsurgically. CONCLUSIONS: Currently, the majority of appendicular fractures in male patients with chronic SCI are managed nonsurgically within the VA health-care system. There is no difference in mortality by type of treatment.

Morbidity following lower extremity fractures in men with spinal cord injury.

UNLABELLED: The Veterans Affairs Spinal Cord Dysfunction Registry from 2002 to 2007 was reviewed to determine whether men with spinal cord injury (SCI) and lower extremity fractures had an increased risk of complications compared to those without fractures. We determined that fractures are associated with significant consequences, particularly during the first month postfracture. INTRODUCTION: Despite increasing longevity, patients with SCI have a substantial number of illnesses and comorbid conditions. Lower extremity fractures are frequent events in these patients. However, whether these fractures are associated with any increased risk of complications in SCI is not certain. The purpose of this report was to determine the impact of lower extremity fractures on morbidities in men with SCI. METHODS: A population-based, nested, case-control (1,027 cases and 1,027 propensity-matched controls) of men enrolled in the Veterans Affairs Spinal Cord Dysfunction Registry from fiscal years 2002 to 2007 was reviewed to determine whether lower extremity fractures were associated with an increased risk for complications. RESULTS: In propensity score models matched for demographic (age, race) and SCI-related injury factors (level/completeness of SCI), Veterans Affairs-service connection status, and comorbidities, at 1 month following the fracture, there was an increased risk for respiratory infections, pressure ulcers, urinary tract infections, thromboembolic events, depression, and delirium (p ≤ 0.03 for all). Over 12 months, the only complication more common in fracture cases was pressure ulcers (p < 0.01), with an absolute difference of less than 2 % when compared to controls. There was no significant increased risk of cardiac arrhythmias at any time examined following fracture (≥0.12). CONCLUSIONS: Lower extremity fractures are associated with significant consequences in men with SCI during the first month postfracture, but they do not persist for a long term, except for pressure ulcers. Targeted interventions to prevent complications should be considered following lower extremity fractures in SCI, particularly in the first month following fracture.

Dysfunctional sleep in persons with spinal cord injuries and disorders.

STUDY DESIGN: Cross-sectional survey of veterans with spinal cord injuries and disorders (SCI/D). OBJECTIVES: To describe sleep dysfunction (independent of sleep apnea) in persons with traumatic and non-traumatic SCI/D, and to examine characteristics and health outcomes independently associated with sleep dysfunction unrelated to sleep apnea. SETTING: Seven Veterans Affairs SCI care facilities in the United States. METHODS: Mailed cross-sectional survey with follow-up calls completed by end of 2008. Bivariate analyses to compare measures outcomes in persons with SCI/D who were dysfunctional sleepers vs those who were not. Multivariate logistic regression used to identify variables independently associated with dysfunctional sleep in veterans with SCI/D. RESULTS: Overall, 49% of the sample had sleep dysfunction unrelated to sleep apnea. In this subgroup, bivariate analyses showed that a greater proportion of dysfunctional sleepers than non-dysfunctional sleepers were current smokers, had problems with drinking alcohol, hypertension, asthma, chronic obstructive pulmonary disease (COPD) and problematic weight gain. Variables independently associated with higher odds of dysfunctional sleep included white race, being a current smoker, problems with drinking alcohol, asthma, COPD and problematic weight gain. CONCLUSION: Consistent with epidemiological evidence for the general population, we found significant associations of sleep dysfunction with weight gain, smoking, alcohol misuse and select chronic conditions (COPD, asthma). Sustained sleep dysfunction may contribute to health deterioration and mortality, highlighting the need to address the high prevalence of sleep dysfunction (independent of sleep apnea) in persons with SCI/D. In particular, efforts aimed at modifying problematic weight gain, alcohol misuse and smoking are warranted in this cohort to improve sleep.

Bloodstream infections and setting of onset in persons with spinal cord injury and disorder.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: Health-care-associated (HCA) bloodstream infection (BSI) has been shown to be a distinct epidemiologic category in the general adult population, but few studies have examined specific patient populations. The objective of this study was to assess characteristics associated with BSI that occurred in the hospital (hospital-acquired, HA BSI), from health-care contact outside the hospital (HCA BSI) or in the community (community-acquired, CA BSI) in veterans with spinal cord injury and disorder (SCI&D). SETTING: Two United States Department of Veterans Affairs hospitals. METHODS: All patients with SCI&D with a positive blood culture admitted to study hospitals over a 7-year period (1 October 1997 to 30 September 2004). Demographics, medical characteristics and causative organisms were collected. RESULTS: Four hundred and thirteen episodes of BSI occurred in 226 patients, with a rate of 7.2 BSI episodes per 100 admissions: 267 (64.7%) were HA BSI, 110 (26.6%) were HCA BSI and 36 (8.7%) were CA BSI. Antibiotic resistance was more common in those with HA BSI (65.5%) compared with that in those with HCA (49.1%, P=0.001) and CA BSI (22.2%, P<0.0001). Methicillin resistance in Staphylococcus aureus was highly prevalent; HA BSI (84.5%), HCA BSI (60.6%) and CA BSI (33.3%). CONCLUSION: HCA BSI comprises one-quarter of all BSIs in hospitalized patients with SCI&D. Although those with HCA and CA BSI share similarities, several differences in medical characteristics and causal microorganism are noted. Treatment and management strategies for HCA and CA infections need to vary.

Management of community-acquired pneumonia in persons with spinal cord injury.

STUDY DESIGN: Retrospective case series. OBJECTIVES: Respiratory disorders are the leading cause of death in persons with spinal cord injury (SCI), but the epidemiology and medical management of pneumonia in persons with chronic SCI is not well characterized. We describe the clinical presentation of persons with SCI with community-acquired pneumonia (CAP), characterize its management and compare practice to recommendations for CAP in the general population. SETTING: Three United States Veterans Affairs Medical Centers with specialized SCI services. METHODS: Chart abstraction was performed for all persons with chronic SCI seen at participating centers for treatment of CAP during a 2-year period. Collected data included presenting signs and symptoms, laboratory and imaging results, initial antibiotic therapy, secretion mobilization techniques, in-patient vs outpatient management, length of stay, and mortality. RESULTS: In all, 41 persons with SCI received treatment for CAP during the study period. A total of 32 (78.0%) patients were admitted for treatment; two (4.8%) required intubation and mechanical ventilation. Initial antibiotic coverage met guideline recommendations for only half of inpatients and infrequently provided adequate antipseudomonal coverage. Microbiologic testing was performed on 26 cases (63.4%) and demonstrated a specific pathogen in only five cases (12.2% of total). Three cases (7.3%) died during treatment for CAP, and 16 (42.1%) of 38 CAP survivors died within a median follow-up of 3 years. CONCLUSION: The majority of chronic SCI patients who present to specialized SCI centers with CAP are admitted for treatment. Short-term mortality is comparable to CAP in the general population.

Lactate supply as a determinant of the distribution of intracellular pH within the hepatic lobule.

When isolated livers from starved rats are perfused with lactate at constant perfusate pH and P(co(2)), there is a marked gradient of cell pH (pH(i)) along the length of the lobular radius, with periportal cells being substantially more alkaline than perivenous cells. In the present studies, the perivenous 21% of the lobular volume was destroyed by retrograde digitonin perfusion, and antegrade perfusion restored. pH(i) was determined by (31)P-NMR. The remaining periportal cells, the site of gluconeogenesis from lactate, had a substantially higher mean pH(i) (7.42) than did the intact liver (7.23). When lactate was removed from the perfusate, mean pH(i) decreased to 7.25. The corresponding concentration of cell bicarbonate fell with a half-time of approximately 5 min. When lactate was re-introduced mean pH(i) rose to 7.34. We conclude that a major contributor to periportal alkalinity under these conditions is proton consumption during gluconeogenesis from lactate ions.

Factors associated with sleep apnea in men with spinal cord injury: a population-based case-control study.

OBJECTIVE: To characterize a population of spinal cord injury (SCI) patients with sleep apnea, and to determine associated factors and comorbidities. STUDY DESIGN: Population-based retrospective case-control study. SUBJECTS: 584 male patients served by a Veterans Affairs SCI service. MEASURES: Medical records were reviewed for sleep apnea diagnosis, demographic information, neurologic characteristics, and treatments received. Sleep study reports were not available to determine the nature of abnormal respiratory events (ie central, obstructive, hypoventilation). For each case with tetraplegia, a control tetraplegic subject without sleep apnea diagnosis was selected. RESULTS: We identified 53 subjects with diagnosed sleep apnea: 42 tetraplegic, 11 paraplegic. This represented 14.9% of all tetraplegic and 3.7% of all paraplegic patients in the population (P<0.0001 for comparison of tetraplegic and paraplegic proportions). In tetraplegic subjects, sleep apnea was associated with obesity and more rostral motor level, but not with ASIA Impairment Scale. Medical comorbidities associated with sleep apnea in non-SCI patients, such as hypertension, were more common in case subjects. Less than half of case subjects were receiving some form of treatment. For motor-complete tetraplegics, long-term positive airway pressure treatment was less common with motor level C5 and above compared to C6 and below. CONCLUSION: In this population, sleep apnea has been frequently diagnosed, particularly in tetraplegic subjects. The true prevalence is likely to be considerably higher, since this study considered only previously diagnosed cases. Sleep apnea was associated with obesity and higher neurologic level, but not ASIA Impairment Scale. Medical comorbidities were more frequent in this group, and treatment acceptance was poor with higher level motor-complete injuries. Since the type of sleep apnea (central or obstructive) was not distinguished, we cannot comment on the prevalence and associations based on specific types of sleep apnea.

Clinician judgments of functional outcomes: how bias and perceived accuracy affect rating.

OBJECTIVE: To evaluate the accuracy of clinician judgments of patient function, the susceptibility of judges to bias, and the relation between a judge's degree of belief in his/her accuracy of classification to observed accuracy when using the FIM instrument. PARTICIPANTS: Fifty rehabilitation professionals. SETTING: 3 urban medical centers. DESIGN: Four randomized experiments among subjects to examine the effect of potentially biasing information on FIM ratings of patient vignettes. Participants answered 60 true/false questions regarding patient function and FIM score and indicated confidence in the accuracy of their answers. INTERVENTIONS: Manipulation of patient information. MAIN OUTCOME MEASURES: The standard FIM 7-point scale, observed proportion of correct responses to the 60 true/false questions, and a 6-category confidence scale for each of the 60 questions were used as dependent measures. RESULTS: FIM ratings assigned to others biased participants' FIM ratings of patient vignettes. Functional ability was overestimated when ratings in other domains were high and underestimated when they were low. Participants were overconfident in their ability to answer FIM questions accurately across all professional disciplines. CONCLUSION: Bias and poor judgment of level accuracy play a significant role in clinician ratings of patient functioning. Blind ratings and training in debiasing are potential solutions to the problem.

Sleep apnea syndrome in chronic spinal cord injury: associated factors and treatment.

OBJECTIVE: To determine the prevalence of sleep apnea in a sample of persons with chronic spinal cord injury (SCI) of varying injury levels and degrees of impairment. DESIGN: Cross-sectional study. SETTING: Inpatient SCI rehabilitation unit. PARTICIPANTS: Twenty men with SCI (motor complete and incomplete; American Spinal Injury Association classes A-D) of at least 1 year's duration, randomly selected from patients with SCI undergoing elective hospitalization. MAIN OUTCOME MEASURES: Apnea index, determined by sleep study (including chest wall movement, airflow, oxygen saturation), and daytime sleepiness, determined by Epworth sleepiness score. RESULTS: Eight subjects (40%) had sleep apnea, manifested by elevated apnea index (mean +/- SD, 17.1 +/- 6.9) and excessive daytime sleepiness. Sleep apnea was commonly diagnosed in motor-incomplete injuries. A trend (p = .07) existed toward a greater prevalence of sleep apnea with tetraplegia. Age and body mass index were not associated with sleep apnea. CONCLUSION: The prevalence of sleep apnea in men with chronic SCI admitted for nonrespiratory elective hospitalization is high relative to the general population.

Investigation of human low-density lipoprotein by (1)H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer.

The resolution of the trimethyl headgroup resonance of phosphatidylcholine (PC) and sphingomyelin (SM) in the intact human low-density lipoprotein (LDL) (1)H NMR spectrum at 600 MHz enabled the investigation of LDL surface structure and phospholipid-apoB interactions. We have previously shown that a higher proportion of PC headgroups (25-35% of total PC in LDL) compared to SM were tightly bound to apoB and therefore NMR-invisible [Murphy, H. C., et al. (1997) Biochem. Biophys. Res. Commun. 234 (3), 733-737]. In the present study, we have investigated the mobility of phospholipid (PL) headgroups, using (1)H NMR spin-spin (T(2)) relaxation measurements, in LDL isolated from nine volunteers. We show that both PC and SM exist in two additional and distinct environments indicated by the biexponential behavior of the relaxation decays in each case. The data showed that 36% of PC headgroups had a short T(2) component, mean T(2) of 31 ms, and 64% had a longer T(2) component of 54 ms. Approximately 15% of SM headgroups had a short T(2) component (mean T(2) of 27 ms) and 85% had a longer T(2) component of 78 ms. Therefore the majority of SM headgroups (85%) were more mobile than PC (P < 0.001) and since PC headgroups in organic media were more mobile than SM, we conclude that the characteristic high mobility of LDL SM is not an intrinsic property but arises from a high degree of order in molecular packing of the surface PL of human LDL. We suggest that because PC and SM interact differentially with cholesterol and possibly with neighboring phospholipids, this results in the formation of relatively long-lived microdomains of PL in vivo.

Hepatic intralobular mapping of fructose metabolism in the rat liver.

Detailed mapping of glucose and lactate metabolism along the radius of the hepatic lobule was performed in situ in rat livers perfused with 1.5 mM lactate before and during the addition of 5 mM fructose. The majority of fructose uptake occurred in the periportal region; 45% of fructose taken up in the periportal half of the lobular volume being converted into glucose. Periportal lactate uptake was markedly decreased by addition of fructose. Basal perivenous lactate output, which was derived from glucose synthesized periportally, was increased in the presence of fructose. During fructose infusion there was a small decrease in cell pH periportally, but acidification of up to 0.5 pH units perivenously. The evidence suggests that in situ the apparent direct conversion of fructose into lactate represents, to a substantial extent, the result of periportal conversion of fructose into glucose and the subsequent uptake and glycolysis to lactate in the perivenous zone of some of that glucose. (31)P NMR spectroscopy showed that the cellular concentration of phosphomonoesters changes very little periportally during fructose infusion, but there was an approximate twofold increase perivenously, presumably due to the accumulation of fructose 1-phosphate. It may be inferred that fructokinase activity is expressed throughout the hepatic lobule.

Fetal programming of hepatic lobular architecture in the rat demonstrated ex vivo with magnetic resonance imaging.

We demonstrate that MRI imaging at sub-millimetre resolution can distinguish between periportal and perivenous zones of the rat liver lobule. This made it possible to measure the hepatic lobular radius in ex-vivo perfused fixed livers using MRI. Comparisons of histomorphometric and MRI measurements of lobular radius were in good agreement, although MRI measurements were significantly smaller (P< 0.001). Male rats whose mothers were fed 40% of the protein of controls during gestation and lactation, had a significantly larger hepatic lobular radius than that of controls [449+/-11 microm vs. 373+/-9 microm (mean +/- SEM), respectively, p<0.001, n = 12; histomorphometry data]. The proton T(2) in periportal and perivenous zones was mapped both before and after antegrade or retrograde perfusion of 10 ml of digitonin (4 mg ml(-1)). Only the T(2) of the hypointense regions increased significantly following antegrade perfusion of digitonin and conversely only that of the intense regions following retrograde perfusion. Digitonin causes permeabilization of cells in specific hepatic zones, determined by the direction of perfusion. The intense and hypointense regions of the hepatic MR images thus arise from the perivenous and periportal zones of the hepatic lobule, respectively.

Neurologic recovery and neurologic decline after spinal cord injury.

Physicians caring for patients with spinal cord injury facilitate neurologic recovery by optimizing nutrition and general health, by coordinating active exercise and functional training to enhance the underlying synapse growth, reversal of muscle atrophy, and motor learning, and by controlling interfering spasticity. SCI physicians also must monitor for neurologic decline during initial rehabilitation and later in life, diagnose promptly and accurately such decline, and orchestrate the appropriate intervention.