Efficacy and adverse effects of insulin versus plasmapheresis in patients with hypertriglyceridemia-3-induced acute pancreatitis: a systematic review and meta-analysis.

Background: Hypertriglyceridemia is a common cause of acute pancreatitis (AP). This literature review compared the effectiveness and adverse events of insulin therapy, with or without heparin, and plasmapheresis, in reducing triglyceride levels in patients with hypertriglyceridemia-induced AP. Methods: Systematic reviews, meta-analyses, evidence syntheses, editorials, commentaries, protocols, abstracts, theses and preprints were excluded. Review Manager was used to conduct the meta-analysis. The literature search yielded 2765 articles, but only 5 were included in the systematic review and meta-analysis and the total number of participants in the review was 269. Results: From this study's analysis, insulin ± heparin was more successful in reducing triglyceride levels than plasmapheresis (standardized mean difference -0.37, 95% confidence interval [CI] 0.99 to 0.25; P=0.25). Insulin ± heparin therapy had a lower mortality rate than plasmapheresis (risk ratio [RR] 0.70, 95%CI 0.25-1.95). Hypotension, hypoglycemia, and acute renal failure were less common in the plasmapheresis therapy group than in insulin ± heparin therapy (RR 1.13, 95%CI 0.46-2.81, RR 3.90, 95%CI 0.45-33.78, and RR 0.48, 95%CI 0.02-13.98 for hypotension, hypoglycemia, and acute renal failure, respectively). Conclusions: This study found no significant difference in mortality between insulin ± heparin therapy and plasmapheresis used for the reduction in triglyceride levels. It is notable that no substantial differences were observed in the most common side-effects encountered during these therapies, thus indicating non-inferiority.

Lack of improvement in anorectal manometry parameters after implementation of a pelvic floor/anal sphincter biofeedback in persons with motor-incomplete spinal cord injury.

BACKGROUND: Effect of biofeedback on improving anorectal manometric parameters in incomplete spinal cord injury is unknown. A short-term biofeedback program investigated any effect on anorectal manometric parameters without correlation to bowel symptoms. METHODS: This prospective uncontrolled interventional study comprised three study subject groups, Group 1: sensory/motor-complete American Spinal Injury Association Impairment Scale (AIS) A SCI (n = 13); Group 2 (biofeedback group): sensory incomplete AIS B SCI (n = 17) (n = 3), and motor-incomplete AIS C SCI (n = 8), and AIS D SCI (n = 6); and Group 3: able-bodied (AB) controls (n = 12). High-resolution anorectal manometry (HR-ARM) was applied to establish baseline characteristics in all subjects for anorectal pressure, volume, length of pressure zones, and duration of sphincter squeeze pressure. SCI participants with motor-incomplete SCI were enrolled in pelvic floor/anal sphincter bowel biofeedback training (2 × 6-week training periods comprised of two training sessions per week for 30-45 min per session). HR-ARM was also performed after each of the 6-week periods of biofeedback training. RESULTS: Compared to motor-complete or motor-incomplete SCI participants, AB subjects had higher mean intra-rectal pressure, maximal sphincteric pressure, residual anal pressure, recto-anal pressure gradient, and duration of squeeze (p < 0.05 for each of the endpoints). No significant difference was evident at baseline between the motor-complete and motor-incomplete SCI groups. In motor-incomplete SCI subjects, the pelvic floor/anal sphincter biofeedback protocol failed to improve HR-ARM parameters. CONCLUSION: Biofeedback training program did not improve anal manometric parameters in subjects with motor-incomplete or sensory-incomplete SCI. Biofeedback did not change physiology, and its effects on symptoms are unknown. INFERENCES: Utility of biofeedback is limited in patients with incomplete spinal cord injury in terms of improving HR-ARM parameters.

Idiosyncratic Drug-Induced Liver Injury Due to Ciprofloxacin: A Report of Two Cases and Review of the Literature.

BACKGROUND Drug-induced liver injury (DILI) can present clinically as a spectrum that includes asymptomatic elevation of transaminases, acute or chronic hepatitis, and acute liver failure. Idiosyncratic DILI is more likely to affect individuals with comorbidities, and to have a wide range of clinical presentations. Although antibiotics are associated with DILI, the fluoroquinolone, ciprofloxacin, is a rarely reported cause. Two cases of idiosyncratic DILI following ciprofloxacin treatment are described, including a review of the literature. CASE REPORT Case 1: A 35-year-old man was treated with ciprofloxacin for periorbital cellulitis. On the second day of ciprofloxacin treatment, he developed abdominal pain, nausea, vomiting and increased serum levels of liver transaminases, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Further investigations excluded infectious hepatitis, autoimmune disease, or structural liver disease. Exclusion of other causes of DILI and cessation of ciprofloxacin resulted in clinical improvement and normalization of liver function tests (LFTs). Case 2: An 82-year-old man was treated with ciprofloxacin for osteomyelitis. On the tenth day of ciprofloxacin treatment, he developed jaundice and abnormal LFTs, including increased AST, ALT, alkaline phosphatase (ALP), and total bilirubin. Further investigations excluded infectious hepatitis, autoimmune disease, or structural liver disease. Exclusion of other causes of DILI and cessation of ciprofloxacin resulted in clinical improvement and normalization of LFTs. CONCLUSIONS Idiosyncratic DILI due to ciprofloxacin treatment is rare. These two cases have shown that timely diagnosis and discontinuation of ciprofloxacin can prevent the progression of DILI, reduce liver damage, and reduce mortality rates from DILI.

Traumatic Spinal Cord Injury: Pulmonary Physiologic Principles and Management.

In the United States, approximately 17,500 cases of traumatic spinal cord injury (SCI) occur each year, with an estimated 245,000 to 345,000 individuals living with chronic SCI. Acute management of respiratory dysfunction has resulted in improvement in early survival, but life expectancy remains less than that of the general population, and pulmonary complications are a leading cause of mortality. The global changes in pulmonary function, underlying pathophysiology, and the management options to improve respiratory muscle weakness and pulmonary clearance in persons with SCI are discussed. Given its high prevalence among subjects with cervical SCI, sleep disordered breathing is also discussed.

Effect of intensive versus standard blood pressure control on major adverse cardiac events and serious adverse events: A bivariate analysis of randomized controlled trials.

BACKGROUND: Intensive blood pressure (BP) lowering may offer protective effects against major adverse cardiac event (MACE) but is also associated with a greater risk of a serious adverse event (SAE). The risk-benefit profile of intensive versus standard BP control has not been comprehensively assessed. METHODS: Four studies were identified from a systematic literature search for randomized controlled trials comparing intensive versus standard BP lowering that reported both MACE and SAE endpoints. A previously described statistical approach was applied to characterize the efficacy-safety tradeoff of BP control. The bivariate outcome was computed to quantitatively assess the net clinical benefit (NCB) of intensive BP lowering as compared to standard treatment, with positive values indicating increased risks and negative values indicating decreased risks. RESULTS: Data from the SPRINT trial demonstrated that intensive strategy was superior in MACE but inferior in SAE, thereby eroding the NCB (bivariate outcome: 0.33% [-0.50% to 1.21%]). Intensive strategy from the SPS3 trial fulfilled non-inferiority in both MACE and SAE but did not reach a favorable NCB (-1.31% [-2.25% to 0.01%]). The ACCORD trial suggested that intensive strategy was non-inferior in MACE but inferior in SAE (-0.19% [-0.79% to 1.37%]). Results from the VALISH trial were inconclusive for SAE but suggested non-inferiority in MACE (-1.19% [-3.24% to 0.68%]). CONCLUSIONS: Compared to the standard blood pressure target, pooled data from randomized controlled trials suggest that intensive strategy did not achieve a net clinical benefit when weighing the benefit of MACE reduction against the risk of SAE under the bivariate framework. ABBREVIATIONS: Blood pressure (BP), diastolic blood pressure (DBP), major adverse cardiac event (MACE), net clinical benefit (NCB), serious adverse event (SAE), systolic blood pressure (SBP).

Dual antithrombotic plus adjunctive antiinflammatory therapy to improve cardiovascular outcome in atrial fibrillation patients with concurrent acute coronary syndrome: A triple-pathway strategy.

The concurrence of atrial fibrillation and acute coronary syndrome poses a conundrum in the antithrombotic management as intensification of anticoagulation or antiplatelet therapy inevitably comes at the price of an increased bleeding risk. Various antithrombotic combinations have been attempted to prevent the recurrent cardiovascular events, however, there has been limited success in effective risk reduction for this high risk population. Given the overarching effect of interleukin 1ß-driven inflammation on the arrhythmogenesis, thrombogenesis, and hypercoagulability, we hypothesize that the triple-pathway strategy (i.e., incorporating antiinflammatory therapy into anticoagulant and antiplatelet therapy) would grant incremental cardiovascular benefits for atrial fibrillation patients with coexisting acute coronary syndrome and stent placement.

Bronchodilator effects of ipratropium bromide and albuterol sulfate among subjects with tetraplegia.

OBJECTIVE: In addition to lung volume restriction, persons with chronic tetraplegia demonstrate obstructive airway physiology evinced by pharmacologically-induced bronchodilation. We previously found independent evidence that anticholinergic agents (ipratropium bromide; IB) and beta-2 adrenergic agonists (albuterol sulfate; AS) were associated with significant bronchodilation in subjects with tetraplegia as determined via spirometry or body plethysmography. Direct comparison of these two classes of agents has received little attention. METHODS: Twelve subjects with chronic tetraplegia completed single dose treatment on alternate days with nebulized IB or AS. Patients underwent pre- and 30-minute post-bronchodilator spirometry, body plethysmography, and impulse oscillation system (IOS) in accordance with established protocols. RESULTS: Spirometry and specific airway conductance revealed significant bronchodilator responsiveness following both IB and AS. As determined by increases in specific airway conductance post-bronchodilator, IB tended toward greater bronchodilation than AS (71% vs. 47%). IOS revealed a greater reduction in central airway resistance (R20) following IB compared to AS (22% vs. 9%, P < 0.01). A greater number of subjects exhibited a clinically significant reduction in R20 following IB compared to AS (58% vs. 8%, P < 0.01). CONCLUSION: Among subjects with tetraplegia, both IB and AS elicit significant bronchodilation, although the magnitude of the bronchodilator response is greater following IB. This lends support to theory of overriding cholinergic airway tone in tetraplegia. The IOS findings further suggest that the predominant site of action of IB is upon the larger central airways congruent with findings in able-bodied subjects.

Delivery of neostigmine and glycopyrrolate by iontophoresis: a nonrandomized study in individuals with spinal cord injury.

STUDY DESIGN: Phase I Clinical Trial. OBJECTIVES: In this proof-of-principle study, the effectiveness and safety of transdermal administration of neostigmine/glycopyrrolate to elicit a bowel movement was compared to intravenous administration in patients with spinal cord injury. SETTING: James J. Peters Veterans Affairs Medical Center (Bronx, NY). METHODS: Individuals were screened for responsiveness (Physical Response) to intravenous neostigmine (0.03 mg/kg)/glycopyrrolate (0.006 mg/kg). Intravenous neostigmine/glycopyrrolate responders (Therapeutic Response) were administered low-dose transdermal neostigmine/glycopyrrolate [(0.05 mg/kg)/(0.01 mg/kg)] by iontophoresis. Non-responders to low-dose transdermal neostigmine/glycopyrrolate were administered high-dose transdermal neostigmine/glycopyrrolate [(0.07 mg/kg)/(0.014 mg/kg)] by iontophoresis. Bowel movement, bowel evacuation time, and cholinergic side effects were recorded. Visits were separated by 2 to 14 days. RESULTS: Eighteen of 25 individuals (72.0%) had a bowel movement (20 ± 22 min) after intravenous neostigmine/glycopyrrolate. Of these 18 individuals, 5 individuals experienced a bowel movement with low-dose transdermal neostigmine/glycopyrrolate. Another five individuals had a bowel movement after high-dose transdermal neostigmine/glycopyrrolate administration. Fewer side effects were observed in individuals who received neostigmine/glycopyrrolate transdermally compared to those who were administered intravenous neostigmine/glycopyrrolate. CONCLUSIONS: Transdermal administration of neostigmine/glycopyrrolate by iontophoresis appears to be a practical, safe, and effective approach to induce bowel evacuation in individuals with spinal cord injury.

The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury.

The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer's disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression. More recently, the UPS has been shown to have vital roles in recovery of function after SCI. The ubiquitin hydrolase (Uch-L1) has been proposed to increase cellular levels of mono-ubiquitin and hence to increase rates of protein turnover by the UPS. A low Uch-L1 level has been linked with Aß accumulation in AD and reduced neuroregeneration after SCI. One likely mechanism for these beneficial effects of Uch-L1 is reduced turnover of the PKA regulatory subunit and consequently, reduced signaling via CREB. The neuron-specific F-box protein Fbx2 ubiquitinates ß-secretase thus targeting it for proteasomal degradation and reducing generation of Aß. Both Uch-L1 and Fbx2 improve synaptic plasticity and cognitive function in mouse AD models. The role of Fbx2 after SCI has not been examined, but abolishing ß-secretase reduces neuronal recovery after SCI, associated with reduced myelination. UBB+1, which arises through a frame-shift mutation in the ubiquitin gene that adds 19 amino acids to the C-terminus of ubiquitin, inhibits proteasomal function and is associated with increased neurofibrillary tangles in patients with AD, Pick's disease and Down's syndrome. These advances in understanding of the roles of the UPS in AD and SCI raise new questions but, also, identify attractive and exciting targets for potential, future therapeutic interventions.

Effects of midodrine and L-NAME on systemic and cerebral hemodynamics during cognitive activation in spinal cord injury and intact controls.

We previously showed that increases in mean arterial pressure (MAP) following administration of midodrine hydrochloride (MH) and nitro-L-arginine methyl ester (L-NAME) resulted in increased mean cerebral blood flow velocity (MFV) during head-up tilt in hypotensive individuals with spinal cord injury (SCI) and question if this same association was evident during cognitive activation. Herein, we report MAP and MFV during two serial subtraction tasks (SSt) given before (predrug) and after (postdrug) administration of MH; (10 mg), L-NAME (1 mg/kg) or no drug (ND) in 15 subjects with SCI compared to nine able-bodied (AB) controls. Three-way factorial analysis of variance (ANOVA) models were used to determine significant main and interaction effects for group (SCI, AB), visit (MH, L-NAME, ND), and time (predrug, postdrug) for MAP and MFV during the two SSt. The three-way interaction was significant for MAP (F = 4.262; P = 0.020); both MH (30 ± 26 mmHg; P < 0.05) and L-NAME (27 ± 22 mmHg; P < 0.01) significantly increased MAP in the SCI group, but not in the AB group. There was a significant visit by time interaction for MFV suggesting an increase from predrug to postdrug following L-NAME (6 ± 8 cm/sec; P < 0.05) and MH (4 ± 7 cm/sec; P < 0.05), regardless of study group, with little change following ND (3 ± 3 cm/sec). The relationship between change in MAP and MFV was significant in the SCI group following administration of MH (r(2) = 0.38; P < 0.05) and L-NAME (r(2) = 0.32; P < 0.05). These antihypotensive agents, at the doses tested, raised MAP, which was associated with an increase MFV during cognitive activation in hypotensive subjects with SCI.

Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury.

Gastrointestinal (GI) dysmotility is a severe, and common complication in patients with spinal cord injury (SCI). Current therapeutic methods using acetylcholine analogs or laxative agents have unwanted side effects, besides often fail to have desired effect. Various ion channels such as ATP-sensitive potassium (KATP) channel, calcium ions (Ca(2+))-activated potassium ions (K(+)) channels, voltage-sensitive Ca(2+) channels and chloride ion (Cl(-)) channels are abundantly expressed in GI tissues, and play an important role in regulating GI motility. The release of neurotransmitters from the enteric nerve terminal, innervating GI interstitial cells of Cajal (ICC), and smooth muscle cells (SMC), causes inactivation of K(+) and Cl(-) channels, increasing Ca(2+) influx into cytoplasm, resulting in membrane depolarization and smooth muscle contraction. Thus, agents directly regulating ion channels activity either in ICC or in SMC may affect GI peristalsis and would be potential therapeutic target for the treatment of GI dysmotility with SCI.

Biomarkers of inflammation in persons with chronic tetraplegia.

In addition to lung volume restriction, individuals with chronic tetraplegia exhibit reduced airway caliber and bronchodilator responsiveness similar to persons with asthma. In asthma, airflow obstruction is closely linked to airway inflammation. Conversely, little is known regarding the airway inflammatory response in tetraplegia. To compare levels of biomarkers of inflammation in exhaled breath condensate (EBC) and serum in subjects with chronic tetraplegia, mild asthma, and able-bodied controls.Prospective, observational pilot study. Thirty-four subjects participated: tetraplegia (n = 12), asthma (n = 12), controls (n = 10). Biomarkers in EBC [8-isoprostane (8-IP), leukotriene B4 (LT-B4), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6)] and serum (8-IP, LT-B4, TNF-α, IL-6) were determined using commercially available EIA kits (Cayman Chemical Company, Ann Arbor, MI). Separate, one-way ANOVA with Bonferroni's post-hoc analyses were performed to determine group differences in demographic and dependent variables [EBC and serum biomarkers, fractional exhaled nitric oxide (FeNO), pulmonary function parameters, and specific airway conductance (sGaw)]. The tetraplegia group had significantly elevated 8-IP levels in EBC compared to the asthma (68 ± 38 versus 21 ± 13 pg ml(-1); p < 0.001) and control groups (22 ± 13 pg ml(-1); p < 0.01), respectively. FeNO levels were significantly elevated in the asthma compared to the control group (26 ± 18 versus 11 ± 4 ppb; p < 0.05), and trended higher than levels in the tetraplegia group (15 ± 6; p = 0.08). Levels of serum biomarkers did not differ significantly among groups. Through analysis of EBC, levels of 8-IP were significantly elevated compared to levels found in individuals with mild asthma and healthy controls. Further studies are needed to extend upon these preliminary findings that suggest the presence of airway inflammation in subjects with chronic tetraplegia, and how this relates to pulmonary dysfunction in this population.

Neostigmine Administered With MoviPrep Improves Bowel Preparation for Elective Colonoscopy in Patients With Spinal Cord Injury: A Randomized Study.

BACKGROUND: Poor preparation for elective colonoscopy is exceedingly common in persons with spinal cord injury (SCI). This unsatisfactory outcome is likely due to long-standing difficulty with evacuation and decreased colonic motility, which may result in inadequate responses to conventional bowel preparation regimens. We determined whether the addition of neostigmine to MoviPrep before elective colonoscopy produced a higher percentage of acceptable bowel preparations in patients with SCI. METHODS: Twenty-seven SCI subjects were prospectively randomized to 1 of 2 arms: low-volume polyethylene glycol-electrolyte lavage with ascorbic acid (MoviPrep) or MoviPrep plus neostigmine methylsulfate and glycopyrrolate (MoviPrep+NG); 28 able-bodied subjects received MoviPrep alone. The quality of the cleansing preparation for colonoscopy was determined by gastroenterologists "calibrated" to use the Ottawa Scoring System, with an acceptable Ottawa Score (OS) considered to be ≤3. RESULTS: The administration of MoviPrep alone resulted in suboptimal bowel cleansing in the SCI group compared with the able-bodied group (50% vs. 89% of subjects had an acceptable OS; χ=7.94, P=0.05). However, when NG was added to MoviPrep in the SCI group, it markedly improved the quality of the bowel preparation, with 85% of patients then having an acceptable OS. The use of NG resulted in minimal bloating and distention before bowel evacuation (P=0.0005), and eye and muscle twitching; these were resolved within 1 hour after NG administration. No significant differences were noted among the preparation groups for adenoma detection rate (P=0.41). CONCLUSIONS: The combination of MoviPrep+NG was safe, well tolerated, and an effective approach to prepare the bowel for elective colonoscopy in patients with SCI. The side effects of this preparation were significant compared with the other treatment groups but were considered mild and anticipated.

Comparison between pulsed irrigation enhanced evacuation and polyethylene glycol-electrolyte lavage solution for bowel preparation prior to elective colonoscopy in veterans with spinal cord injury.

BACKGROUND: Poor preparation for elective colonoscopy is common in persons with spinal cord injury (SCI). This unsatisfactory outcome is likely due to long-standing difficulty with evacuation and decreased colonic motility. Our objective was to determine the most effective preparation for elective colonoscopy applying a novel and traditional approach to bowel cleansing. METHODS: Twenty-four subjects with SCI were consented and scheduled to receive one of the two possible arms: pulsed irrigation enhanced evacuation (PIEE) or polyethylene glycol-electrolyte lavage solution (PEG; CoLyte(®)). The quality of the preparation was scored during the colonoscopy by applying the Ottawa scoring system. RESULTS: Patients with SCI who received PIEE tended to have lower Ottawa scores and a higher percentage of acceptable preparations than did those who received PEG; however, the results were not statistically different. CONCLUSION: In this preliminary study in subjects with SCI, neither PIEE nor PEG produced acceptable bowel preparation for elective colonoscopy. Future studies should confirm our findings and consider studying alternative, more efficacious approaches to bowel cleansing prior to colonoscopic procedures in patients with SCI, which should provide better outcomes. Registration number for clinicaltrials.gov: NCT00745095.

A center's experience: pulmonary function in spinal cord injury.

Traumatic spinal cord injury (SCI) is associated with significant psychological and physical challenges. A multidisciplinary approach to management is essential to ensure recovery during the acute phase, and comprehensive rehabilitative strategies are necessary to foster independence and quality of life throughout the chronic phase of injury. Complications that beset these individuals are often a unique consequence of SCI, and knowledge of the effects of SCI upon organ systems is essential for appropriate management. According to the National SCI Statistical Center (NSCISC), as of 2010 there were an estimated 265,000 persons living with SCI in the United States, with approximately 12,000 incidence cases annually. Although life expectancy for newly injured individuals with SCI is markedly reduced, persons with chronic SCI are expected to live about as long as individuals without SCI; however, longevity varies inversely with level of injury. Since 2005, 56 % of persons with SCI are tetraplegic, and due to paralysis of respiratory muscles, these individuals may be especially prone to pulmonary complications, which remain a major cause of mortality among persons with chronic SCI. We at the VA Rehabilitation Research and Development Center of Excellence for the Medical Consequences of SCI at the James J. Peters VA Medical Center have devoted more than 25 years to the study of secondary medical conditions that complicate SCI. Herein, we review pulmonary research at the Center, both our past and future endeavors, which form an integral part of our multidisciplinary approach toward achieving a greater understanding of and improving care for veterans with SCI.

The hemodynamic actions of insulin are blunted in the sublesional microvasculature of healthy persons with spinal cord injury.

OBJECTIVE: The aim of this study was to gain a better understanding of the hemodynamic actions of insulin on cutaneous microcirculation in persons with spinal cord injury (SCI). DESIGN: A prospective, open-label, nonrandomized, placebo-controlled investigation was performed in an otherwise healthy cohort of persons with SCI (n = 10) and in an age- and sex-matched cohort of control subjects whose neurologic function is intact (n = 10). Laser Doppler flowmetry characterized the peak blood perfusion unit (BPU) response (percent change from baseline) to insulin or placebo iontophoresis above and below the neurologic level of injury. RESULTS: Placebo iontophoresis did not result in any statistically significant changes in BPU. In the arm, insulin iontophoresis resulted in a 20% mean increase in BPU (P < 0.05) in the control group and a 9% mean increase in the SCI group (P = 0.14). In the leg, insulin iontophoresis resulted in an 81% (P < 0.01) mean increase in BPU in the control group and a 29% (P < 0.001) mean increase in BPU in the SCI group. The relative effect of insulin on the lower extremity BPU response was significantly greater (P < 0.05) in the control group compared with the SCI group (77% vs. 35%, respectively). CONCLUSIONS: The hemodynamic actions of insulin are markedly blunted in the sublesional microvasculature of persons with SCI, most likely as a result of impaired sublesional sympathetic nervous system control.

31st g. Heiner sell lectureship: secondary medical consequences of spinal cord injury.

Persons with spinal cord injury (SCI) have secondary medical consequences of paralysis and/or the consequences of extreme inactivity. The metabolic changes that result from reduced activity include insulin resistance with carbohydrate disorders and dyslipidemia. A higher prevalence of coronary artery calcification was found in persons with SCI than that in matched able-bodied controls. A depression in anabolic hormones, circulating testosterone and growth hormone, has been described. Adverse soft tissue body composition changes of increased adiposity and reduced skeletal muscle are appreciated. Immobilization is the cause for sublesional disuse osteoporosis with an associated increased risk of fragility fracture. Bowel dysmotility affects all segments of the gastrointestinal tract, with an interest in better defining and addressing gastroesophageal reflux disease and difficulty with evacuation. Developing and testing more effective approaches to cleanse the bowel for elective colonoscopy are being evaluated. The extent of respiratory dysfunction depends on the level and completeness of SCI. Individuals with higher spinal lesions have both restrictive and obstructive airway disease. Pharmacological approaches and expiratory muscle training are being studied as interventions to improve pulmonary function and cough strength with the objective of reducing pulmonary complications. Persons with spinal lesions above the 6th thoracic level lack both cardiac and peripheral vascular mechanisms to maintain blood pressure, and they are frequently hypotensive, with even worse hypotension with upright posture. Persistent and/or orthostatic hypotension may predispose those with SCI to cognitive impairments. The safety and efficacy of anti-hypotensive agents to normalize blood pressure in persons with higher level cord lesions is being investigated.

Orthostatic effects of midodrine versus L-NAME on cerebral blood flow and the renin-angiotensin-aldosterone system in tetraplegia.

OBJECTIVE: To compare responses to head-up tilt (HUT) in individuals with chronic tetraplegia after midodrine hydrochloride (10 mg) versus nitro-L-arginine methyl ester (L-NAME, 1 mg/kg) administration. DESIGN: Prospective comparative drug trial. SETTING: Veterans Affairs medical center. PARTICIPANTS: Participants (N=7) were studied during 3 laboratory visits: no drug, midodrine (administered orally 30 min before HUT), and L-NAME (infused over a 60-min period). INTERVENTIONS: Anti-hypotensive agents, midodrine, and L-NAME. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), cerebral blood flow (CBF), and markers of the renin-angiotensin-aldosterone system (RAAS, plasma renin and serum aldosterone) were measured in the supine position at baseline (BL) and during a 45° HUT maneuver. Data were compared between BL and the average of 3 assessments collected during HUT. RESULTS: Orthostatic MAP and CBF were increased with the midodrine and L-NAME groups compared with the no drug trial and the relationship between the change in MAP and CBF was significant (r=0.770; P<0.001). Both L-NAME and midodrine appeared to suppress the post-HUT RAAS response compared with no drug. CONCLUSIONS: Increasing orthostatic blood pressure with L-NAME or midodrine appears to increase CBF and suppress the RAAS during HUT in persons with tetraplegia, although more data are needed to confirm these preliminary findings.

Effects of midodrine hydrochloride on blood pressure and cerebral blood flow during orthostasis in persons with chronic tetraplegia.

OBJECTIVE: To determine the mean arterial pressure (MAP) and middle cerebral artery mean blood flow velocity (MFV) responses to 5 and 10mg midodrine during head-up tilt (HUT) in persons with tetraplegia. DESIGN: Prospective dose-response trial. SETTING: James J. Peters Veterans Administration Medical Center. PARTICIPANTS: Persons (N=10) with chronic tetraplegia (duration of injury=23+/-11 y). INTERVENTION: A dose titration study was performed over 3 testing days: control (no drug), 5mg midodrine (5mg), or 10mg midodrine (10mg) during 30 minutes of baseline (predrug/no drug), 30 minutes of supine rest postdrug/no drug, 15 minutes of progressive HUT (5 minutes at 15 degrees , 25 degrees , 35 degrees ), and 45 minutes of 45 degrees HUT. MAIN OUTCOME MEASURES: MAP and MFV response to midodrine supine and during HUT. RESULTS: Ten milligrams of midodrine significantly increased MAP while supine and during the HUT maneuver. Of note, the mean increase in MAP during HUT with 10mg was a result of a robust effect in 2 persons, with minimal change in the remaining 8 study subjects. The reduction in cerebral MFV during HUT was attenuated with 10mg. CONCLUSIONS: These findings suggest that midodrine 10mg may be efficacious for treatment of hypotension and orthostatic hypotension in select persons with tetraplegia. Although midodrine is routinely prescribed to treat orthostatic hypotension, the results of our work suggests limited efficacy of this agent, but additional studies in a larger sample of subjects with spinal cord injury should be performed.

Exhaled nitric oxide levels are elevated in persons with tetraplegia and comparable to that in mild asthmatics.

The role of airway inflammation in mediating airflow obstruction in persons with chronic traumatic tetraplegia is unknown. Measurement of the fraction of exhaled nitric oxide (FeNO) affords a validated noninvasive technique for gauging the airway inflammatory response in asthma, although it has never been assessed in persons with tetraplegia. This study was designed to determine the FeNO in individuals with chronic tetraplegia compared with that in patients with mild asthma and healthy able-bodied individuals. Nine subjects with chronic tetraplegia, seven subjects with mild asthma, and seven matched healthy able-bodied controls were included in this prospective, observational, pilot study. All subjects were nonsmokers and clinically stable at the time of study. Spirometry was performed on all participants at baseline. FENO was determined online by a commercially available closed circuit, chemiluminescence method, using a single-breath technique. Subjects with tetraplegia had significantly higher values of FeNO than controls (17.72 +/- 3.9 ppb vs. 10.37 +/- 4.9 ppb; P < or = 0.01), as did subjects with asthma (20.23 +/- 4.64 ppb vs. 10.37 +/- 4.9 ppb, P < or = 0.001). There was no significant difference in FeNO between subjects with tetraplegia and those with asthma (17.72 +/- 3.9 ppb vs. 20.23 +/- 4.64 ppb, P < or = 0.27). Individuals with chronic tetraplegia have FeNO levels that are comparable to that seen in mild asthmatics and higher than that in healthy able-bodied controls. The clinical relevance of this observation has yet to be determined.