Dwindally Rosado-Rivera

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.

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.

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.

The QT Variability Index and Cardiac Autonomic Modulation: Perspectives from Apparently Healthy Men with Spinal Cord Injury

Objective: To describe the effect of spinal cord injury (SCI) on the QT variability index (QTVI). Methods: Digital electrocardiograms from 113 age-matched men (40 with tetraplegia, 26 with high paraplegia, 17 low paraplegia and 31 controls) were analyzed. RR interval, heart rate (HR) variability [total power (TPRR), low frequency (LFRR) and high frequency (HFRR)], QT interval duration, Bazett HR-corrected QT (QTc), QT interval variance (QTVN) and QTVI were compared. Results: Significant group main effects were present for RR, QTc, TPRR and LFRR, but not QT duration, QTVN or HFRR. Post hoc comparisons revealed the following: (1) longer RR in controls versus subjects with high paraplegia and low paraplegia, and in subjects with tetraplegia versus high paraplegia and low paraplegia; (2) QTc was longer in subjects with low paraplegia versus controls and shorter in subjects with tetraplegia versus high paraplegia, and (3) TPRR and LFRR were different in controls and subjects with high paraplegia compared to those with low paraplegia. QTVI was significantly elevated in all SCI groups compared to controls. Significant negative correlations between QTVI and HFRR were observed in all SCI groups, and TPRR and LFRR in subjects with tetraplegia and high paraplegia only. Age was negatively correlated in controls. Conclusions: QTVI is negatively affected in otherwise healthy SCI men compared to age-matched controls. This observation appears to reflect the attenuation of vagal modulation, sympathetic impairment above the sixth thoracic vertebra and/or a heightened degree of cardiovascular disease risk.

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.

Hemodynamic Effects of l-Threo-3,4-Dihydroxyphenylserine (Droxidopa) in Hypotensive Individuals With Spinal Cord Injury

OBJECTIVES To determine the effect of an escalating dose of droxidopa (100, 200, and 400 mg) compared with placebo on seated blood pressure (BP) in hypotensive individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effect of droxidopa on (1) supine BP and heart rate, (2) the change in BP and heart rate when these individuals were transferred from the supine to the seated position, and (3) adverse event (AE) reporting. DESIGN Open-label dose titration trial. SETTING A Veterans Administration Medical Center. PARTICIPANTS Participants with SCI (C3-T12) (N=10) were studied during 4 laboratory visits. Subjects visited the laboratory for about 5 hours on each visit, which incorporated a 30-minute seated baseline, a 30- to 60-minute supine, and a 4-hour seated postdrug observation. INTERVENTIONS Placebo on visit 1, droxidopa 100 mg on visit 2, droxidopa 200 mg on visit 3, and droxidopa 400 mg on visit 4. MAIN OUTCOME MEASURES BP and heart rate changes from baseline to the postdrug period, orthostatic heart rate and BP responses, and subjective AE reporting. RESULTS Seated BP was significantly elevated with 400 mg droxidopa compared with placebo and 100 mg droxidopa for 3 hours and was elevated for 2 hours compared with 200 mg droxidopa. Increase in supine BP was not worsened following droxidopa, and the expected fall in BP when transferred to the seated position was prevented with droxidopa 200 and 400 mg. There were no significant differences in the heart rate response or AE reporting among the study visits. CONCLUSIONS Our preliminary findings suggest that droxidopa, at the doses tested, does not cause excessive increases in supine BP and the 400-mg dose appears to be effective at increasing seated BP for up to 3 hours in persons with SCI.

Effect of Mild Cold Exposure on Cognition in Persons with Tetraplegia

UNLABELLED Persons with a cervical spinal cord injury (SCI) have impaired thermoregulatory mechanisms secondary to interrupted of motor, sensory, and sympathetic pathways. In this study, our primary aim was to determine the effect of cool temperature exposure on core body temperature (Tcore) and cognitive performance in persons with tetraplegia. Seven men with chronic tetraplegia (C3-C7, American Spinal Injury Association Impairment Scale [AIS] A-C) and seven able-bodied controls were exposed to 27°C temperature at baseline (BL) before being exposed to 18°C for ≤120 min (Cool Challenge). Rectal temperature (Tcore), distal skin temperatures (Tskavg), microvascular skin perfusion (LDFavg), and systolic blood pressure (SBP) were measured. Cognitive performance was assessed using Delayed Recall, Stroop Interference tests at the end of BL and Cool Challenge. After Cool Challenge, Tcore decreased -1.2±0.12°C (p<0.0001) in tetraplegics after an average of 109±15.9 min with no change in controls after 120 min. Tskavg declined in both groups, but decline was less in tetraplegics than in controls (-8.6±5.8% vs. -31.6±7.9%, respectively; p<0.0001). LDFavg declined only in controls (-72±17.9%; p<0.001). Plasma norepinephrine levels differed after Cool Challenge (tetraplegics vs. CONTROLS 86±62 pg/mL vs. 832±431 pg/mL, respectively; p<0.01). SBP increased from BL to Cool Challenge only in controls (123±16 mm Hg to 149±17 mm Hg, respectively; p<0.01). Delayed Recall and Stroop Interference scores both declined in tetraplegics (-55±47.4%; p<0.05 and -3.9±3.8%; p<0.05, respectively), but not in controls. We conclude that persons with tetraplegia lack adequate thermoregulatory mechanisms to prevent downward drift in Tcore on exposure to cool temperatures. This decline in Tcore was associated with deterioration of working memory and executive function.

Self-reported effects of cold temperature exposure in persons with tetraplegia

Objective: Cervical spinal cord injury (tetraplegia) is known to interrupt sympathetic vasculature control, thereby preventing shunting of blood from the periphery to central organs when exposed to cold temperatures. As a result, persons with tetraplegia are at risk to develop hypothermia. However, information regarding the discomfort experienced during the cooler months (late fall, winter, early spring) is overwhelmingly anecdotal. It is not known, with any certainty, how those with tetraplegia perceive cold and if discomfort in colder environments restricts them from performing activities that they routinely would perform. Design: Prospective, two-group, self-report surveys. Setting: VA Medical Center and Kessler Institute for Rehabilitation. Participants: Forty-four subjects with tetraplegia; 41 matched non-SCI controls. Outcome Measures: Tetraplegic and control groups responded “yes” or “no” when asked whether cold seasonal temperatures allowed comfort or negatively affected participation in routine activities. Results: Percentage of responses of tetraplegia compared to controls was different as to whether they felt cold when others in the same room were comfortable (82 vs. 24%; χ2 = 28.2, P < 0.0001), felt comfortable outdoors (17 vs. 43%; χ2 = 6.8, P = 0.009), or whether cold negatively affected bathing routines (55 vs. 15%; χ2 = 14.8, P = 0.0001), keeping physician appointments (46 vs. 12%; χ2 = 11.3, P = 0.0008), thinking clearly (41 vs. 7%; χ2 = 12.9, P = 0.0003), and completing usual work duties (46 vs. 10%; χ2 = 13.3, P = 0.0003). Conclusion: Cold seasonal temperatures have a reported greater negative impact on personal comfort and ability to perform vital activities in persons with tetraplegia than that of non-SCI controls. These findings highlight the need to address thermoregulatory impairment in persons with tetraplegia.