Effects of Midodrine Hydrochloride on Blood Pressure and Cerebral Blood Flow During Orthostasis in Persons with Chronic Tetraplegia Jill M

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ORIGINAL ARTICLE Effects of Midodrine Hydrochloride on Blood Pressure and Cerebral Blood Flow During Orthostasis in Persons With Chronic Tetraplegia Jill M. Wecht, EdD, Dwindally Rosado-Rivera, EdD, John P. Handrakis, PT, EdD, Miroslav Radulovic, MD, William A. Bauman, MD

ABSTRACT. Wecht JM, Rosado-Rivera D, Handrakis JP, Key Words: Hypotension, orthostatic; Midodrine; Rehabil- Radulovic M, Bauman WA. Effects of midodrine hydrochlo- itation; Spinal cord injuries; Tilt-table test. ride on blood pressure and cerebral blood flow during ortho- © 2010 by the American Congress of Rehabilitation stasis in persons with chronic tetraplegia. Arch Phys Med Medicine Rehabil 2010;91:1429-35. Objective: To determine the mean arterial pressure (MAP) N PERSONS WITH SPINAL cord injury, in addition to motor and middle cerebral artery mean blood flow velocity (MFV) Iand sensory deficits, partial or complete interruption of auto- responses to 5 and 10mg midodrine during head-up tilt (HUT) nomic cardiovascular innervation results in dysregulation of blood in persons with tetraplegia. pressure. Although the etiology may vary, the prevailing thought Design: Prospective dose-response trial. is that blood pressure disorders in persons with tetraplegia derive Setting: James J. Peters Veterans Administration Medical from decentralized sympathetic neural cardiovascular control, and Center. significantly reduced plasma norepinephrine levels have been Participants: Persons (Nϭ10) with chronic tetraplegia (du- reported during HUT.1-3 As a consequence of impaired sympa- ration of injuryϭ23Ϯ11y). thetic cardiovascular innervation, individuals with tetraplegia are Intervention: A dose titration study was performed over 3 prone to chronic hypotension with exacerbations during periods of testing days: control (no drug), 5mg midodrine (5mg), or 10mg orthostasis.4-8 It is well established that OH hinders the rehabili- midodrine (10mg) during 30 minutes of baseline (predrug/no tation process during the acute and subacute phases of SCI4,9-11 drug), 30 minutes of supine rest postdrug/no drug, 15 minutes but may also hamper the resumption of independence and func- of progressive HUT (5 minutes at 15°, 25°, 35°), and 45 tional activities in persons with chronic SCI.6,10 We recently minutes of 45° HUT. reported significantly reduced memory and marginally reduced Main Outcome Measures: MAP and MFV response to attention and processing speed and executive function in hypo- midodrine supine and during HUT. tensive persons with chronic SCI compared with normotensive Results: Ten milligrams of midodrine significantly in- counterparts,12 as previously reported in the non-SCI popula- creased MAP while supine and during the HUT maneuver. Of tion.13-17 Thus, chronic hypotension and OH might be expected to note, the mean increase in MAP during HUT with 10mg was a limit significantly the quality of life in persons with SCI, and result of a robust effect in 2 persons, with minimal change in treatment options should be considered. the remaining 8 study subjects. The reduction in cerebral MFV Although many persons with tetraplegia are hypotensive, during HUT was attenuated with 10mg. they often remain clinically asymptomatic, and, for this reason, Conclusions: These findings suggest that midodrine 10mg treatment strategies are not routinely considered as part of may be efficacious for treatment of hypotension and orthostatic clinical care. In fact, there is a striking disparity between the hypotension in select persons with tetraplegia. Although mido- available treatment options for hypertension compared with drine is routinely prescribed to treat orthostatic hypotension, hypotension in the general population: hypertension has 119 the results of our work suggests limited efficacy of this agent, U.S. Food and Drug Administration–approved medications, but additional studies in a larger sample of subjects with spinal and hypotension just 1, midodrine hydrochloride. Of note, the cord injury should be performed. safety and efficacy of midodrine for the treatment of chronic hypotension and OH has not been formally tested in the SCI population. The results of several case reports on the use of midodrine to treat OH in person’s with SCI suggest improved From the James J. Peters Veterans Administration Medical Center, Bronx, NY, blood pressure and reduced symptoms of cerebral hypoper- Center of Excellence (Wecht, Rosado-Rivera, Handrakis, Radulovic, Bauman), and the Medical Service (Wecht, Radulovic, Bauman), the Mount Sinai School of Med- icine, New York; Departments of Medicine (Wecht, Radulovic, Bauman) and Reha- bilitation Medicine (Wecht, Radulovic, Bauman); NYIT—School of Health Profes- List of Abbreviations sions, Old Westbury (Handrakis), NY. Presented to the Congress of Spinal Cord Medicine and Rehabilitation, September AD autonomic dysreflexia 24, 2009, Dallas, TX. Supported by the Veterans Affairs Rehabilitation Research and Development CBF cerebral blood flow Service (grant nos. A6161W, B3203R, B4162C). HUT head-up tilt No commercial party having a direct financial interest in the results of the research MAP mean arterial pressure supporting this article has or will confer a benefit on the authors or on any organi- MCA middle cerebral artery zation with which the authors are associated. Reprint requests to Jill M. Wecht, EdD, Center of Excellence: Medical Conse- MFV mean blood flow velocity quences of Spinal Cord Injury, James J. Peters VA Medical Center, Room 1E-02, 130 OH orthostatic hypotension West Kingsbridge Rd, Bronx, NY 10468, e-mail: [email protected]. SCI spinal cord injury 0003-9993/10/9109-00307$36.00/0 TCD transcranial Doppler doi:10.1016/j.apmr.2010.06.017

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Table 1: Subject Characteristics

Subject No. Sex Age (y) HT (cm) WT (kg) BMI DOI (y) Level AIS 1 Man 27 175 66 21.4 9 C5 ASIA grade A 2 Man 44 180 66 20.2 30 C4-5 ASIA grade C 3 Man 36 165 70 25.8 10 C5-6 ASIA grade A 4 Woman 55 168 62 22.1 39 C7 ASIA grade B 5 Man 38 188 77 21.8 13 C4-5 ASIA grade A 6 Man 47 180 82 25.1 23 C5-6 ASIA grade B 7 Man 42 165 84 30.8 13 C4-5 ASIA grade A 8 Man 43 163 59 22.1 26 C5-6 ASIA grade A 9 Woman 35 173 51 17.2 17 C5-6 ASIA grade A 10 Man 57 183 62 18.4 39 C5-7 ASIA grade B Average 42.4 174.0 67.8 22.5 21.9 SD 9.1 8.6 10.4 3.9 11.3

Abbreviations: AIS, American Spinal Injury Association Impairment Scale; ASIA, American Spinal Injury Association; HT, height; WT, weight; BMI, body mass index; DOI, duration of injury; Level, level of SCI. fusion (ie, dizziness, fatigue, blurred vision, syncope, light- drug (control); visit 2, midodrine 5mg; visit 3, midodrine 9,11 headedness). Reduction in the cerebral symptoms of hypo- 10mg. On arrival at the laboratory, between 8:00 and 10:00 AM, tension should be reflected in preserved CBF during orthostasis subjects were transferred to the tilt table in the supine posi- after midodrine administration, although this has not been tion for a minimum of 20 minutes for instrumentation. Three reported in the SCI population. ECG electrodes were applied to the chest for continuous The objective of this study was to determine the dose-response heart rate monitoring.a Blood pressure was measured at the for blood pressure and CBF after midodrine administration while brachial artery by a trained clinician by using a standard supine and during a HUT maneuver in persons with chronic adult blood pressure cuffb placed around the left upper arm. tetraplegia. We hypothesized that systemic blood pressure would CBF was estimated from MFV of the left MCA by using be increased in a dose-response manner after midodrine adminis- TCD ultrasound technology.c After instrumentation, base- tration, and the increase in systemic blood pressure would be line data were collected for heart rate, blood pressure, and associated with a dose-response increase in CBF. MFV at 0 and 20 minutes. Midodrine hydrochloride 5 or METHODS 10mg was administered orally with a glass of water 30 minutes into testing; subjects were not given any medication Subjects on the control visit, and additional supine data were col- Ten subjects with chronic tetraplegia volunteered to participate; lected at 35, 45, and 55 minutes prior to the tilt maneuver. the demographics of the study group are presented (table 1). No Because the blood pressure effects of midodrine are gener- study subject had a history of cardiovascular disease, none were ally demonstrated within minutes and peak effects are ex- prescribed medications with known cardiovascular or autonomic pected within an hour of administration, the progressive effects, and none were current smokers. All study participants HUT maneuver began 30 minutes after midodrine adminis- were neurologically stable for at least 9 years postinjury and were tration, and subjects remained in the orthostatic position for recruited from the Center of Excellence for the Medical Conse- a total of 60 minutes thereafter (ie, 90min after midodrine quences of Spinal Cord Injury at the James J. Peters Veterans administration). The tilt table was padded and motorized; Affairs Medical Center. The study protocol was approved by the restraining straps were used on the lower extremities and local institutional review board with strict adherence to the stan- trunk to ensure subject safety and were padded to avoid dards established in the Helsinki Declaration. Written informed stimulation of sympathetic spinal reflexes during testing. consent was obtained before performing the study procedures. Adjustment of the tilt table to the desired angle was accom- plished in less than 5 seconds, and the progressive HUT Study Procedures maneuver consisted of 5 minutes at each intermediate angle The study time line is presented (fig 1); 10 subjects with of tilt (15°, 25°, 35°) and 45 minutes at 45°. A progressive tetraplegia underwent 3 separate days of testing: visit 1, no HUT maneuver was used to allow adequate time for activa- tion of the renin-angiotensin system, the predominant mech- anism used for blood pressure control in individuals with tetraplegia.18 Subjects were questioned at 10-minute intervals for the presence of the symptoms of hypotension and cerebral hypoperfusion (ie, dizziness, fatigue, blurred vision, syncope, lightheadedness). Heart rate was monitored continuously with an ECG signal recorded from a 3-lead configuration. Electrodes were placed at the distal right and left clavicle, and the recording electrode was placed in the left lateral fifth intercostal space (V-5) by using standard skin-abrading and hair-shaving methods as needed. Manual blood pressure was measured by auscultation at the brachial artery and was recorded by a trained clinician Fig 1. The timeline for study procedures. The thin arrows represent twice at baseline, 3 times postdrug while the subject was in the data collection time points; the thick arrow represents midodrine supine position, and once at each angle of progressive HUT, administration. and 4 measurements were taken at 15-minute intervals while

Arch Phys Med Rehabil Vol 91, September 2010 TREATMENT OF HYPOTENSION IN SPINAL CORD INJURIES, Wecht 1431 the subject was at 45°. MAP (mmHg) was calculated from brachial pressures as follows: [systolic ϩ (2 * diastolic)] ⁄ 3 To determine MFV, a TCD probe was operated at a fre- quency of 2.0MHz to visualize the left MCA, and insonation was through the temporal window. The MCA was identified by the target depth (45-55mm), sound and direction of flow (ie, toward the probe), the characteristic spectral waveform, relatively faster flow velocity compared with other cerebral ves- sels, and compression of the common carotid artery, which resulted in an appropriate reduction in MCA flow velocity. Once the MCA was visualized, a head harness was used to secure the probe position for the duration of testing, and MFV (cm/s) was calculated as follows: [peak systolic velocity ϩ (2 * end diastolic velocity) ⁄ 3] MCA MFV is an accepted surrogate of CBF, which has been validated and reported by several investigators.19-21 TCD signals were channeled and stored on a hard drive for future analysis by using customized data acquisition and analysis programs written with LabVIEW graphic software for instrumentation.d Data Analysis Data are reported as mean Ϯ SD. Repeated-measures analysis of variance was used to determine within-subject differences in mean heart rate, blood pressure, and MFV responses to no drug, 5mg, and 10mg midodrine. A repeated-measures analysis of variance was used to determine significant dose (no drug, 5mg, 10mg), condition (baseline, postdrug, transition, HUT), and interaction effects for heart rate, blood pressure, and MFV. Fisher post hoc analyses were used to explore significant omnibus effects further. Significance was set at the .05 alpha level. RESULTS Demographic characteristics of the study group are presented (see table 1). Subjects were between 27 and 57 years of age and a minimum of 9 years postinjury, with levels of lesions between C4 and C7; 9 were motor-complete American Spinal Injury Association Impairment Scale grades A and B; all were nonambulatory. Although 1 individual (patient 3) developed significant symptoms of syncope that led to early termination of the HUT maneuver on the no drug visit, and there was a trend toward reduced orthostatic symptoms after midodrine administration, in general, OH symptoms reporting did not differ significantly among the study visits (table 2). Fig 2. The response to study visit: control (open circles), 5mg The MAP, heart rate, and MFV response to study visit and (closed triangles) and 10mg (closed squares), and condition (bl, condition are presented (fig 2). There was a significant main postdrug, transition, HUT) for MAP (A, mmHg), heart rate (B, bpm) and MFV (C, cm/s). There were significant condition main effects for MAP, heart rate, and MFV (P<.0001), and the interaction effect was significant for MAP (P<.01) and MFV (P<.05). The main effect for Table 2: Symptoms Reporting During HUT study visit was not significant for MAP, heart rate, or MFV. NOTE. The letters a, b, c, d are 4 time points of data collection at 45° HUT. Symptom No Drug 5mg 10mg Abbreviation: bl, baseline. Sleepy 1 0 0 Nausea 0 1 0 Lightheadedness 3 2 0 effect for condition and interaction effects for MAP, heart rate, Yawning 3 1 0 and MFV. In general, heart rate was increased and MAP and Fatigue 3 0 0 MFV tended to be reduced during the HUT maneuver regard- Pallor 1 0 0 less of the study visit. MAP was increased during the supine Dizziness 0 1 0 postdrug period and during the transition with 10mg midodrine Heated 1 3 2 compared with the control visit (PϽ.05); however, a progres- Blurry vision 0 0 0 sive decline in MAP was evident during the sustained HUT Neck pain 1 0 0 maneuver. There were no significant main or interaction effects Total 13 8 2 for MAP, heart rate, or MFV between the control and 5mg midodrine study visits.

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Table 3: Mean Date at Supine, Postdrug, and 45° HUT thostasis.4-8 The extent of autonomic impairment and the car- No Drug 5mg 10mg P diovascular consequences may or may not relate to the level of SCI.6 Although midodrine is the most commonly prescribed Heart rate (bpm) pharmacologic agent for treatment of OH in this population, Supine 59Ϯ13 57Ϯ862Ϯ13 NS convincing scientific data are lacking. This is the first system- Postdrug 60Ϯ14 57Ϯ10 59Ϯ11 NS atic investigation to document the effects of midodrine hydro- HUT 70Ϯ15 64Ϯ967Ϯ11 NS chloride on systemic blood pressure during orthostasis in indi- SBP (mmHg) viduals with tetraplegia. The results suggest that, compared Supine 98Ϯ597Ϯ5 102Ϯ12 NS with the control visit, the 5-mg dose of midodrine had little Postdrug 102Ϯ11 102Ϯ11 107Ϯ15 NS effect on increasing MAP during a HUT maneuver. Although HUT 87Ϯ15 97Ϯ17 109Ϯ22* Ͻ.05 the 10-mg dose of midodrine increased MAP during HUT DBP (mmHg) compared with the control HUT maneuver, individual re- Supine 64Ϯ661Ϯ863Ϯ7NS sponses varied considerably and do not support the general use Postdrug 64Ϯ966Ϯ10 69Ϯ9* Ͻ.05 of this medication for treatment of OH in this population. HUT 62Ϯ13 64Ϯ772Ϯ17 NS Several case reports have been published on the effects of MAP (mmHg) midodrine to increase orthostatic blood pressure and reduce Supine 75Ϯ573Ϯ676Ϯ7NS symptoms of OH in individuals with SCI.9,11,22 The results of Postdrug 78Ϯ677Ϯ882Ϯ8NS these case studies suggest that midodrine is safe and efficacious HUT 70Ϯ13 73Ϯ984Ϯ17* Ͻ.05 MCA MFV (cm/s) Supine 55Ϯ12 52Ϯ10 55Ϯ15 NS Postdrug 53Ϯ13 51Ϯ956Ϯ16 NS HUT 48Ϯ845Ϯ10 52Ϯ13 NS

NOTE. Data are mean Ϯ SD. Abbreviations: DBP, diastolic blood pressure; MCA MFV, middle cerebral artery mean ﬂow velocity; NS, not signiﬁcant; SBP, systolic blood pressure. *Versus no drug.

Mean data for the heart rate, blood pressure, and MFV response to dose and condition are presented (table 3). There were no differences for baseline supine heart rate, blood pressure, or MFV. Supine diastolic blood pressure and MAP were increased after 10mg midodrine compared with the control visit (PϽ.05). During the 45° HUT maneuver, systolic blood pressure and MAP were increased after 10mg midodrine compared with the control visit (PϽ.05). There were no significant effects for heart rate, blood pressure, or MFV when comparing 5mg midodrine and the control visit, or between the 5-mg and 10-mg doses of midodrine. The mean change from baseline in heart rate, MAP, and MFV is presented (fig 3). On average, the change in MAP was increased after 10mg midodrine during the supine postdrug period and during the sustained HUT maneuver compared with the control visit (PϽ.05). There were no differences among study visits for the change in heart rate. However, 10mg midodrine attenuated the fall in MFV during HUT compared with the control visit (Pϭ.05). Although, on average, MAP was increased after the 10-mg dose of midodrine during supine rest and HUT compared with the control visit, individual responses varied (fig 4). During the supine period, 10mg midodrine (see fig 4A) seemed to increase MAP in most subjects compared with their control visit; during the HUT maneuver, however, the data are less convincing (see fig 4B). It is apparent that 2 individuals had an augmented response to 10mg midodrine during HUT (subjects 5 [closed triangle] and 9 [ϩ]). Also, 1 subject appeared to respond better to the 5-mg dose than to the 10-mg dose of midodrine (subject 1 [closed square]), and 1 subject had the highest MAP response to HUT during the control visit (subject 11 [open circle]). DISCUSSION

Individuals with tetraplegia are a model of decentralized Fig 3. The mean change from baseline in MAP (A), heart rate (B), sympathetic cardiovascular control, which may result in and MFV (C) after no drug (white bars), 5mg midodrine (checked chronic hypotension with exacerbations during periods of or- bars), and 10mg midodrine (black bars). *P<.05 versus no drug.

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ment of hypotension and OH in the SCI population. It should be appreciated that, because of alpha-1 receptor hyperrespon- siveness,31 blood pressure elevations during AD may be exac- erbated with midodrine administration in persons with high cord lesions. Although several reports have documented the utility of midodrine to increase the likelihood of ejaculation during sexual stimulation in persons with SCI,32-35 the observed increase in blood pressure with midodrine administration and ejaculation was not augmented compared with ejaculation alone.33 In contrast, AD associated with bladder distension was reported in 2 individuals with tetraplegia due to increased sphincter tone after midodrine administration for the treatment of OH.36 Because AD is often unpredictable and the blood pressure elevations may be severe and life-threatening, caution and close clinical observation should be maintained when prescribing midodrine for the treatment of OH in individuals with SCI. Compromise in cerebral blood flow is presumed to be responsible for the clinical symptoms of hypotension (ie, dizziness, fatigue, blurred vision, syncope, lightheadedness),37 and there is documentation of reductions in these symptoms after treatment with midodrine in individuals with neurogenic OH28,29 and SCI.9,11 Midodrine reportedly does not cross the blood-brain barrier38; however, direct evidence of the effects of midodrine on CBF is limited. Significantly reduced MCA MFV has been reported in persons with chronic hypotension,14 and improvement in CBF was documented after acute administration of midodrine.39 In contrast, a 4-week treatment with midodrine (4mg/d) did not significantly improve CBF during HUT in hemodialysis patients with OH.40 The present data suggest that the reduction in MCA MFV during HUT was attenuated with 10mg midodrine compared with the control HUT, which Fig 4. Individual MAP responses to no drug, 5mg midodrine, and was most likely related to increased systemic blood pressure. 10mg midodrine during the supine postdrug/no drug period (A) and However, because only 1 subject developed significant symp- during the sustained HUT maneuver at 45° (B). toms of cerebral hypoperfusion during the control HUT maneuver, we were unable to determine improvement in the clinical symptoms of OH after midodrine administration. for use in individuals with SCI to treat OH associated with An increased prevalence of OH has been reported in the SCI rehabilitation activities during the acute period after injury. In population,4,6-8 and the diagnosis of OH has been as high as the only placebo-controlled randomized trial, 10mg midodrine 74% during orthostatic maneuvers and mobilization in the increased systolic blood pressure during maximal exercise in 3 acute rehabilitation setting.8 It is also well established that the individuals with chronic tetraplegia; 1 individual did not re- risk of developing OH during orthostatic maneuvers is in- spond to the medication.23 Based on these limited data, how- creased in high cord lesions.4,6-8 The mechanisms responsible ever, several review articles suggest that midodrine should be for OH in persons with SCI have been investigated and include considered for use in individuals with SCI for treatment of loss of descending supraspinal sympathetic control5,41 associ- OH.4,9-11,24 Our data indicate that midodrine may have utility ated with low circulating plasma norepinephrine and epineph- for the management of OH in select patients with SCI. How- rine levels,3,5 morphologic changes within the sympathetic ever, the effects of midodrine on supine, seated, and upright nervous system,24 and increased nitric oxide production in blood pressure should be determined on an individual basis in association with vascular vasodilatation.42 The etiology of OH persons with SCI to document the therapeutic effect prior to in persons with SCI is multifactorial, and treatment approaches prescribing this agent. should reflect the variety of pathologic mechanisms. Prior to Midodrine is an alpha-1 agonist that exerts effects via acti- prescribing midodrine for treatment of hypotension and OH in vation of the alpha-adrenergic receptors on the vascular walls, patients with SCI, nonpharmacologic remedies should be con- thereby increasing vessel tone and blood pressure.25-27 Mido- sidered. These include using abdominal and leg binders, in- drine is the only U.S. Food and Drug Administration–approved creasing daily salt and water intake, raising the head of the bed medication for the treatment of OH, and its efficacy has been 10° to 20° at nighttime, and minimizing daily intake of diuret- documented in conditions of central and peripheral autonomic ics such as caffeine and alcohol.43 impairment.28,29 There is evidence to suggest that midodrine elicits a larger blood pressure effect in conditions of postgan- Study Limitations glionic (ie, diabetic neuropathy, pure autonomic failure, etc.) Because of safety concerns, our study was designed as a compared with preganglionic (ie, multiple system atrophy) dose-response trial of 5-mg and 10-mg doses of midodrine disorders.30 The utility in persons with SCI, a preganglionic compared with a control HUT maneuver. A matching placebo sympathetic disorder, is therefore uncertain, although there is tablet was not used and the order of testing was not random- evidence of increased sensitivity to an alpha-1 agonist in 1 ized, which are limitations to data interpretation. In addition, individual with SCI compared with 6 controls without SCI.22 controls without SCI were not recruited, and, therefore, the As such, alpha-1 agonists may have clinical utility for treat- blood pressure and MFV responses during HUT after mido-

Arch Phys Med Rehabil Vol 91, September 2010 1434 TREATMENT OF HYPOTENSION IN SPINAL CORD INJURIES, Wecht drine in the SCI population cannot be compared with a re- 12. Jegede AB, Rosado-Rivera D, Bauman WA, et al. Cognitive sponse of a control without SCI. The total number of subjects performance in hypotensive persons with spinal cord injury. Clin recruited was relatively small, and extrapolation to a broader Auton Res 2010;20:3-9. more heterogeneous group of individuals with chronic SCI may 13. Duschek S, Matthias E, Schandry R. Essential hypotension is not be appropriate. Furthermore, because the blood pressure accompanied by deficits in attention and working memory. Behav responses varied among this small cohort of subjects, these Med 2005;30:149-58. preliminary results do not support the utility of midodrine for 14. Duschek S, Schandry R. Cognitive performance and cerebral treatment of OH in persons with SCI. Finally, caution should blood flow in essential hypotension. Psychophysiology 2004;41: be exercised prior to prescribing midodrine to individuals with 905-13. SCI who experience frequent bouts of AD. 15. Duschek S, Schandry R. Deficient adjustment of cerebral blood flow to cognitive activity due to chronically low blood pressure. CONCLUSIONS Biol Psychol 2006;72:311-7. 16. Duschek S, Schandry R. Reduced brain perfusion and cognitive To our knowledge, this study is the first systematic report on performance due to constitutional hypotension. Clin Auton Res the efficacy of midodrine for treatment of OH in individuals 2007;17:69-76. with SCI. The findings suggest that mean blood pressure was 17. Duschek S, Weisz N, Schandry R. Reduced cognitive perfor- increased during HUT after 10mg midodrine compared with mance and prolonged reaction time accompany moderate hypo- the control HUT maneuver; the 5-mg dose of midodrine did not tension. Clin Auton Res 2003;13:427-32. significantly increase orthostatic blood pressure. The signifi- 18. Wecht JM, Radulovic M, Weir JP, Lessey J, Spungen AM, Bau- cant increase in MAP during HUT was largely a result of an man WA. Partial angiotensin-converting enzyme inhibition during augmented response in 2 subjects; the other 8 individuals acute orthostatic stress in persons with tetraplegia. J Spinal Cord demonstrated a change in MAP during tilt that was similar to Med 2005;28:103-8. the study visit without medication. Furthermore, an augmented 19. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial MAP response to 5mg compared with 10mg midodrine was Doppler ultrasound recording of flow velocity in basal cerebral observed in 1 subject. Thus, because of the variability in arteries. J Neurosurg 1982;57:769-74. response to midodrine and the heterogeneous etiology of hy- 20. Bishop CC, Powell S, Rutt D, Browse NL. Transcranial Doppler potension in the SCI population, medications with different measurement of middle cerebral artery blood flow velocity: a mechanisms of action should be considered and developed for validation study. Stroke 1986;17:913-5. use in the treatment of hypotension and OH in this population. 21. Larsen FS, Olsen KS, Hansen BA, Paulson OB, Knudsen GM. Transcranial Doppler is valid for determination of the lower limit References of cerebral blood flow autoregulation. Stroke 1994;25:1985-8. 1. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Goodwin TJ, 22. Senard JM, Arias A, Berlan M, Tran MA, Rascol A, Monta- Peart WS. Plasma catecholamines, plasma renin activity and struc JL. Pharmacological evidence of alpha 1- and alpha plasma aldosterone in tetraplegic man, horizontal and tilted. Clin Sci Mol Med 1975;49:291-9. 2-adrenergic supersensitivity in orthostatic hypotension due to 2. Mathias CJ, Christensen NJ, Frankel HL, Peart WS. 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