Miroslav Radulovic

Pulmonary function and spinal cord injury

Injury to the cervical and upper thoracic spinal cord disrupts function of inspiratory and expiratory muscles, as reflected by reduction in spirometric and lung volume parameters and static mouth pressures. In association, subjects with tetraplegia have decreased chest wall and lung compliance, increased abdominal wall compliance, and rib cage stiffness with paradoxical chest wall movements, all of which contribute to an increase in the work of breathing. Expiratory muscle function is more compromised than inspiratory muscle function among subjects with tetraplegia and high paraplegia, which can result in ineffective cough and propensity to mucus retention and atelectasis. Subjects with tetraplegia also demonstrate heightened vagal activity with reduction in baseline airway caliber, findings attributed to loss of sympathetic innervation to the lungs. Significant increase in airway caliber following inhalation of ipratropium bromide, an anticholinergic agent, suggests that reduction in airway caliber is not due to acquired airway fibrosis stemming from repeated infections or to abnormal hysteresis secondary to chronic inability of subjects to inhale to predicted total lung capacity. Reduced baseline airway caliber possibly explains why subjects with tetraplegia exhibit airway hyperresponsiveness to methacholine and ultrasonically nebulized distilled water. While it has been well demonstrated that bilateral phrenic nerve pacing or stimulation through intramuscular diaphragmatic electrodes improves inspiratory muscle function, it remains unclear if inspiratory muscle training improves pulmonary function. Recent findings suggest that expiratory muscle training, electrical stimulation of expiratory muscles and administration of a long-acting beta(2)-agonist (salmeterol) improve physiological parameters and cough. It is unknown if baseline bronchoconstriction in tetraplegia contributes to respiratory symptoms, of if the chronic administration of a bronchodilator reduces the work of breathing and/or improves respiratory symptoms. Less is known regarding the benefits of treatment of obstructive sleep apnea, despite evidence indicating that the prevalence of this condition in persons with tetraplegia is far greater than that encountered in able-bodied individuals.

Comparison of 24-hour cardiovascular and autonomic function in paraplegia, tetraplegia, and control groups: implications for cardiovascular risk.

Abstract Background Fluctuations in 24-hour cardiovascular hemodynamics, specifically heart rate (HR) and blood pressure (BP), are thought to reflect autonomic nervous system (ANS) activity. Persons with spinal cord injury (SCI) represent a model of ANS dysfunction, which may affect 24-hour hemodynamics and predispose these individuals to increased cardiovascular disease risk. Objective To determine 24-hour cardiovascular and ANS function among individuals with tetraplegia (n = 20; TETRA: C4–C8), high paraplegia (n = 10; HP: T2–T5), low paraplegia (n = 9; LP: T7–T12), and non-SCI controls (n = 10). Twenty-four-hour ANS function was assessed by time domain parameters of heart rate variability (HRV); the standard deviation of the 5-minute average R–R intervals (SDANN; milliseconds/ms), and the root-mean square of the standard deviation of the R–R intervals (rMSSD; ms). Subjects wore 24-hour ambulatory monitors to record HR, HRV, and BP. Mixed analysis of variance (ANOVA) revealed significantly lower 24-hour BP in the tetraplegic group; however, BP did not differ between the HP, LP, and control groups. Mixed ANOVA suggested significantly elevated 24-hour HR in the HP and LP groups compared to the TETRA and control groups (P < 0.05); daytime HR was higher in both paraplegic groups compared to the TETRA and control groups (P < 0.01) and nighttime HR was significantly elevated in the LP group compared to the TETRA and control groups (P < 0.01). Twenty-four-hour SDANN was significantly increased in the HP group compared to the LP and TETRA groups (P < 0.05) and rMSSD was significantly lower in the LP compared to the other three groups (P < 0.05). Elevated 24-hour HR in persons with paraplegia, in concert with altered HRV dynamics, may impart significant adverse cardiovascular consequences, which are currently unappreciated.

Infusion of Neostigmine–Glycopyrrolate for Bowel Evacuation in Persons with Spinal Cord Injury

Defecatory complications are common after spinal cord injury (SCI) and have been attributed, in part, to an imbalance of the autonomic nervous system between parasympathetic and sympathetic effects on the colon. Because parasympathetic (i.e., cholinergic) input to the bowel may be downregulated after SCI, it was hypothesized that neostigmine, a medication that increases cholinergic tone by blocking the metabolism of acetylcholine, might promote bowel evacuation in these persons. Since neostigmine is known to cause bradycardia and bronchoconstriction, we also assessed whether these side-effects could be prevented by coadministration of neostigmine with glycopyrrolate, an anticholinergic agent that has limited activity on the muscarinic receptors of the colon. The hypothesis was tested in 13 persons with SCI in whom videofluoroscopy was carried out after instillation of a barium oatmeal paste into the rectum and descending colon. On separate days, subjects received, in a randomized, blinded design, one of three intravenous infusates (normal saline, 2 mg neostigmine, or 2 mg neostigmine + 0.4 mg glycopyrrolate). The effect of these infusates on bowel evacuation of the barium paste, heart rate, and airway resistance was determined. Both neostigmine and neostigmine + glycopyrrolate resulted in prompt bowel evacuation. The nadir heart rate was lower after neostigmine alone than with the combination. Neostigmine administration increased both total and central airway resistance, an effect that was not observed with the coadministration of glycopyrrolate. Other side-effects of neostigmine and the combination of drugs included muscle fasciculations and dry mouth, both of which were mild and short-lived. Abdominal cramping was noted in subjects with spinal cord lesions below thoracic level 10. These results indicated that neostigmine/glycopyrrolate administration is safe and well tolerated in persons with chronic SCI.

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 Aβ 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 β-secretase thus targeting it for proteasomal degradation and reducing generation of Aβ. 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 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.

Partial Angiotensin–Converting Enzyme Inhibition During Acute Orthostatic Stress in Persons With Tetraplegia

Abstract Introduction: Individuals with tetraplegia rely on the renin-angiotensin system for orthostatic blood pressure control. Objectives: To determine the effect of partial angiotensin-converting enzyme (ACE) inhibition on heart rate (HR), active plasma renin (PR), and mean arterial blood pressure (MAP)during acute orthostasis in subjects. with tetraplegia (n = 7) and nondisabled persons (n = 8). Methods: Subjects were instructed to avoid caffeine and alcohol for 24 hours before testing and to report to the laboratory between 1 0 AM and 1 PM. Progressive head-up tilt (15°,25°, 35°, and 45°)was performed on 2 separate days; Day 1 : without ACE inhibition; Day2:after intravenous (IV) infusion of enalaprilat (0.625mg). Results: HR was reduced during orthostasis in the tetraplegia compared with the nondisabled group(P < 0.0001 ), and was unaffected by ACE inhibition in either group. PR was not increasedwith orthostasis in either group, but was increased after ACE inhibition in both groups (P < 0.001 ). MAP wasnot affected by orthostasis in either group, but was reduced with ACEinhibition in both groups (P < 0.01).In the tetraplegia group, MAP was initially reducedafter ACE inhibition, but was maintained thereafter withincreasing angles of tilt,and nosubject complainedof symptomatic orthostatic hypotension. Conclusion: Subjects with tetraplegia were tolerant of an acute bout of orthostatic stress after partial ACE inhibition. This may have clinical relevance because of the increasedprevalence of type 2 diabetes mellitus in this population and the use of ACE inhibitors for the treatment ofprogressive renal and cardiovascular disease.

Airflow Obstruction and Reversibility in Spinal Cord Injury: Evidence for Functional Sympathetic Innervation

OBJECTIVES The first objective was to assess group differences for specific airway conductance (sGaw) among subjects with tetraplegia, high paraplegia (HP: T2-T6), and low paraplegia (LP: T10-L4). The second objective was to determine the significance of responsiveness to ipratropium bromide (IB) by the assessment of the inherent variability of baseline measurements for impulse oscillation (IOS), body plethysmography, and spirometry. DESIGN Prospective cross-sectional intervention study. SETTING James J. Peters Veterans Administration Medical Center. PARTICIPANTS Subjects (N=43): 12 with tetraplegia (C4-8), 11 with HP, 11 with LP, and 9 controls. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Measurement of IOS, body plethysmography, and spirometry parameters at baseline and 30 minutes after IB. RESULTS Baseline sGaw was significantly lower in tetraplegia (0.14+/-0.03) compared with HP (0.19+/-0.05) and LP (0.19+/-0.04) patients. By use of minimal difference to evaluate IB responsiveness in tetraplegia, 4 of 12 and 12 of 12 subjects had significant increases in forced expiratory volume in 1 second and sGaw, respectively, whereas 11 of 12 and 10 of 12 subjects had significant decreases in respiratory resistances measured at 5 and 20 Hz (R5 and R20), respectively. CONCLUSIONS The finding of group differences for baseline sGaw supports the hypothesis that human lung contains functional sympathetic innervation. Body plethysmography and IOS were comparable in detecting IB-induced bronchodilation in tetraplegia and significantly more sensitive than spirometry.

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.

Orthostatic Responses to Nitric Oxide Synthase Inhibition in Persons With Tetraplegia

OBJECTIVES To determine the effects of 1.0 mg/kg nitro-L-arginine methyl ester (L-NAME) on orthostatic mean arterial pressure (MAP), serum aldosterone, and plasma renin concentrations in persons with chronic tetraplegia compared with nonspinal cord-injured controls. DESIGN Prospective placebo-controlled intervention study. SETTING James J. Peters Veterans Affairs Medical Center. PARTICIPANTS Patients (n=5) with tetraplegia and controls (n=7) participated. The groups were matched for age, height, and weight; the average duration of injury in the tetraplegia group was 22+/-14 years. INTERVENTION Subjects with tetraplegia visited the laboratory twice, receiving placebo on day 1 and L-NAME (1.0 mg/kg) on day 2. The agents were infused via an intravenous catheter over 60 minutes with the patient in the supine position. Data were collected during the infusion and then during head-up tilt to 45 degrees for 30 minutes. Control subjects visited the laboratory once for placebo infusion and the head-up tilt maneuver. MAIN OUTCOME MEASURE Orthostatic MAP. RESULTS Orthostatic MAP was reduced after placebo infusion in subjects with tetraplegia compared with controls (69+/-11 vs 89+/-9 mmHg, respectively; P<.01) and compared with L-NAME infusion (90+/-16 mmHg; P<.01). Orthostatic MAP did not differ when comparing the tetraplegia group with controls after L-NAME infusion. Orthostatic aldosterone levels were increased after placebo compared with L-NAME infusion in persons with tetraplegia; plasma renin levels did not differ among the groups. CONCLUSIONS These data suggest that nitric oxide synthase inhibition may have clinical potential for treatment of orthostatic hypotension in persons with chronic tetraplegia.