Abstract
Acetylcholine (Ach) is the pre-synaptic neurotransmitter of the sympathetic nervous system. Increased pre-synaptic Ach may augment post-synaptic release of norepinephrine thereby increasing systemic blood pressure (BP). The primary objective of this investigation was to determine the hemodynamic effect of pyridostigmine bromide (PYRIDO: 60 mg), an Ach inhibitor (AchI), compared to no-drug (NO-D) during head-up tilt (HUT) in individuals with spinal cord injury (SCI). Secondarily we aimed to determine the effects of PYRIDO compared to NO-D on symptoms of orthostatic intolerance (OI) and adverse event reporting (AE). Ten individuals with SCI (C4–C7) were studied on 2 occasions: visit 1) NO-D and visit 2) PYRIDO. On each visit subjects underwent a progressive HUT maneuver to 15°, 25°, 35° for 5 minutes at each angle and 45 minutes at 45°. Supine and orthostatic heart rate (HR), systolic and diastolic BP (SBP & DBP) were monitored and symptoms of OI and AE recorded. Supine hemodynamics did not differ between the trials. The significant fall in SBP during the NO-D trial was diminished with PYRIDO and five subjects had an increased DBP during HUT with PYRIDO compared to the NO-D trial. Individuals that responded to PYRIDO with an increase in orthostatic BP had significantly lower resting HR than non-responders (p<0.01), which suggests increased levels of pre-synaptic Ach. Subjective symptoms of OI and AE reporting did not differ between the two trials. These preliminary data suggest that PYRIDO is safe and may be effective at ameliorating the orthostatic fall in BP in select individuals with SCI.
Introduction
De-centralized autonomic nervous system (ANS) control of the cardiovascular system in persons with tetraplegia often results in chronic hypotension and/or orthostatic hypotension (OH).1–4 Although many individuals with tetraplegia remain asymptomatic during periods of significant hypotension, associations between persistent and episodic asymptomatic hypotension and cognitive dysfunction5–7 and mood disorders8, 9 is reported in the general medical literature. Moreover, our group recently reported reduced memory and marginally impaired attention processing in hypotensive individuals with spinal cord injury (SCI) compared to a normotensive SCI cohort.10 Thus, we believe that treatment of asymptomatic hypotension and OH in the SCI population may be clinically warranted.
Midodrine hydrochloride (midodrine) and more recently L-threo-3,4-dihydroxyphenylserine (droxidopa) have been approved by the FDA for use in treatment of orthostatic dizziness in patients with symptomatic neurogenic OH; however, proof of efficacy in the SCI population is limited. In hypotensive individuals with SCI we reported a significant increase in orthostatic blood pressure (BP) following a single dose of midodrine (10 mg) in 2 of the 10 subjects tested.11 Whereas droxidopa (400 mg), in an open label dose escalation trial, normalized systolic BP (SBP: ≥110 mmHg) in 6 of the 10 subjects tested.12 It must be appreciated that BP responses to midodrine and droxidopa varied among hypotensive individuals with SCI, which underscores the need to identify pharmacological agents with different mechanisms of action for treatment of hypotension and OH in the SCI population.
The ANS has a unique neuro-anatomic structure that differs from the somatic and motor nervous systems in that, pre-ganglionic cholinergic nerves synapse with peripheral nerves in the autonomic ganglia within the brain stem and the spinal cord, and the pre-synaptic neurotransmitter is acetylcholine (Ach). Synaptic transmission in the peripheral autonomic ganglia is integral to post-synaptic ANS function; therefore, potentiation of the pre-synaptic signal may improve peripheral autonomic function. Acetylcholinesterase inhibition (AchI) has been used experimentally to treat OH in models of autonomic dysfunction,13–19 and the orthostatic BP response to AchI was equivalent in models of central (i.e., multiple system atrophy) and peripheral (i.e., pure autonomic failure and autonomic neuropathies) ANS dysfunction.18 The model of SCI represents central ANS dysfunction, and partial preservation of pre-ganglionic ANS transmission may be evident in individuals with an incomplete autonomic lesion. Because we cannot directly assess the level or completeness of an autonomic lesion in persons with SCI, we believe that individuals with an orthostatic BP response to AchI may have an incomplete autonomic lesion.
The purpose of this investigation was to compare supine and orthostatic BP and heart rate (HR) responses to oral administration of pyridostigmine bromide (PYRIDO: 60 mg) compared to a no drug trial (NO-D) in individuals with SCI. In addition, symptoms of orthostatic intolerance (OI) (i.e., light headedness, fatigue, blurred vision, dizziness, nausea, headache, faint, other) and adverse side effects (AE) were compared between the PYRIDO and a NO-D trial.
Methods
All study participants were recruited from the National Center of Excellence for the Medical Consequences of Spinal Cord Injury satellite center located in West Orange, New Jersey at the Kessler Institute for Rehabilitation (KIR). The study protocol was approved by the local Institutional Review Board (IRB) at KIR and by the James J Peters VAMC IRB, with strict adherence to the standards established in the Helsinki Declaration. Written informed consent was obtained before performing any study procedure in our subjects.
Subjects
Prior to enrollment in the study, potential subjects underwent a screening laboratory BP assessment to document hypotension as defined by the World Health Organization (W.H.O.) criteria (i.e., ≤110 mmHg for males and ≤100 mmHg for females).20 Seventeen subjects were screened for eligibility, 2 were screening failures because they were not hypotensive, and 15 were enrolled in the parent protocol. Subsequent to enrollment, 5 were excluded from participation due to comorbid conditions (n=3; autonomic dysreflexia (AD), diabetes mellitus, prescription anti-HTN medication) and the inability to complete the head-up tilt (HUT) procedure (n=2; contractures, frequent need to catheterize). Eligible participants were asked to refrain from caffeine for 12-hours and food for 4-hours prior to study. Complete study procedures were carried-out in 10 healthy volunteers with SCI on 2 separate laboratory visits; each study visit was 3–4 hours in duration. On the first laboratory visit study subjects underwent a HUT maneuver without drug (NO-D). On the second study visit subjects participated in an identical HUT maneuver 30 minutes after oral ingestion of PYRIDO (Mestinon, 60 mg, Valeant Pharmaceuticals International, Aliso Viejo CA).
Study Procedures
Upon arrival to the laboratory subjects were transferred to the tilt table and remained in the supine position for instrumentation, which included placement of three ECG electrodes for continuous HR monitoring (IVY 101NR, IVY Biomedical Systems Inc. Branford, CT) and placement of a brachial BP cuff (Finometer Midi, Finapress Medical Systems, Amsterdam, Netherlands) for periodic BP recording. The ECG electrodes were placed at the distal right and left clavicle and the recording electrode was placed in the left lateral 5th intercostal space (V-5), the skin was prepared using standard abrading and hair-shaving methods, as needed. Brachial BP was measured using a standard adult BP cuff placed around the left upper arm and BP was recorded throughout the study using manual auscultation. Subjects remained in the supine position on the tilt table for an hour and baseline (BL) HR and BP were observed and 5-minute averages were recorded at 25-minute intervals (visit 2: pre-PYRIDO: 0–5 minutes, 25–30 minutes and visit 2: post-PYRIDO: 55–60 minutes). PYRIDO was administered orally 30 minutes into the supine BL period on study visit 2; the study timeline is presented (Figure 1).
Figure 1.
Depicts the study timeline.
After the 60 minute supine observation period, and 30 minutes after ingestion of PYRIDO on visit 2, subjects underwent a progressive HUT maneuver to 15°, 25°, and 35° for 5 minutes in each position followed by 45 minutes in the 45° HUT position. HR was continuously monitored during the HUT procedure and BP was recorded every minute. In addition, symptoms of OI and AE reporting were assessed every 10 minutes during the HUT maneuver.
Data Analysis
Data were analyzed using SPSS version 21. To determine the effects of PYRIDO on supine hemodynamics, the difference between the average of time-points 0–5 and 25–30 minutes (pre-PYRIDO) and the 55–60 minute time-point (post-PYRIDO) were compared between the NO-D and PYRIDO trials using paired analyzes. Repeated measures analysis of variance models were calculated to determine statistically significant main (i.e., VISIT and HUT) and interaction effects (VISIT × HUT) for the HR and BP response to the HUT maneuver (i.e., 0°, 15°, 25°, 35°, 45°). Change from BL to the average hemodynamic response at 45° HUT was compared between the NO-D and the PYRIDO trial using paired t-tests. The difference between visits in the HR response to 45° HUT was calculated as ((HRPYRIDO – HRNO-D)/ HRNO-D)*100 (similar equations were calculated for SBP and DBP); statistical significance was determined using a one-sample t-test. The frequency and severity of the symptoms of OI were compared between the NO-D and the PYRIDO trials using paired t-test analysis. Data are reported as mean ± standard deviation; statistical significance was set at α level of 0.05.
Results
Subject Characteristics
Demographic characteristics of the study participants are presented (Table 1). The age range of the participants was 21–51 years, and all were chronically injured (1–33 years). There was 1 female participant; all had a cervical lesion (C4–C7) and 7 of the 10 participants were motor and sensory complete according to their American Spinal Injury Association Injury Scale (AIS) classification. The order of testing was not randomized and there was, on average, 2-weeks between study visits.
Table 1.
Subject Characteristics
| ID | Sex | Age | HT (cm) | WT (kg) | DOI (yrs) | LOI | AIS | Days |
|---|---|---|---|---|---|---|---|---|
| K01 | Male | 45 | 163 | 70 | 28 | C5–6 | A | 33 |
| K02 | Male | 32 | 188 | 84 | 4 | C6 | A | 12 |
| K03 | Male | 51 | 180 | 76 | 12 | C5 | B | 14 |
| K05 | Female | 37 | 173 | 50 | 21 | C5–6 | A | 21 |
| K08 | Male | 32 | 175 | 73 | 8 | C5–6 | A | 14 |
| K09 | Male | 50 | 185 | 73 | 25 | C5 | C | 22 |
| K10 | Male | 21 | 188 | 82 | 3 | C5 | C | 1 |
| K11 | Male | 40 | 173 | 66 | 22 | C6 | A | 14 |
| K12 | Male | 47 | 173 | 70 | 4 | C7 | A | 14 |
| K13 | Male | 28 | 183 | 111 | 12 | C4–5 | A | 7 |
| mean±std | 38±10 | 178±8 | 76±16 | 14±9 | 15±9 | |||
HT=height; WT=weight; DOI=duration of injury (years); LOI=level of injury
AIS=American Spinal Injury Classification Scale; Days=days in between visits
Supine Hemodynamics
Average baseline data are presented for time points 0–5 and 25–30 minutes (Table 2); there were no significant differences in supine hemodynamics between the visits. Change in supine hemodynamics from pre-PYRIDO to post-PYRIDO is presented (Figure 2A–C). There were no significant effects of PYRIDO on supine hemodynamics compared to NO-D visit. However, in 6 of the study participants, an increase in supine SBP was observed following PYRIDO compared to the average change in SBP during the NO-D trial (Figure 2B).
Table 2.
Supine Hemodynamics
| Subject | HR | SBP | DBP | |||
|---|---|---|---|---|---|---|
| NO-D | PYRIDO | NO-D | PYRIDO | NO-D | PYRIDO | |
| K01 | 55 | 50 | 78 | 92 | 51 | 56 |
| K02 | 51 | 49 | 115 | 107 | 80 | 69 |
| K03 | 55 | 53 | 107 | 98 | 72 | 65 |
| K05 | 78 | 65 | 103 | 91 | 73 | 62 |
| K08 | 56 | 49 | 99 | 100 | 62 | 65 |
| K09 | 66 | 57 | 117 | 115 | 77 | 73 |
| K10 | 47 | 48 | 92 | 87 | 51 | 56 |
| K11 | 52 | 53 | 95 | 90 | 61 | 58 |
| K12 | 41 | 45 | 124 | 109 | 70 | 68 |
| K13 | 55 | 54 | 98 | 82 | 68 | 66 |
| mean±std | 55±10 | 52±6 | 103±14 | 97±11 | 66±10 | 64±6 |
Figure 2.
Displays the change in supine hemodynamics during the NO-D (closed circles) and PYRIDO 60 mg (open squares) trials. Data reflect the change from pre- (BL time-points 0 and 25 minutes) to post- (BL time-point 55 minutes) for HR [A], SBP [B] and DBP [C]. There were no significant effects of PYRIDO compared to NO-D for supine hemodynamics.
Orthostatic Hemodynamic Effect
Average hemodynamic responses to the progressive HUT maneuver are presented (Table 3); compared to the NO-D trial, orthostatic HR was significantly reduced following PYRIDO, but the average orthostatic BP response did not differ between the two study visits. Individual hemodynamic responses to the progressive HUT maneuver are presented for the NO-D and PYRIDO trials (Figure 3). Although the main effect for VISIT and the interaction effect were not significant, the main effect for HUT was significant for each hemodynamic parameter (p<0.05). Change in hemodynamics from BL to 45° HUT is presented comparing the NO-D to the PYRIDO trial (Figure 4A–C). The increase in HR with HUT was significant regardless of trial (p<0.01). The significant fall in SBP noted during the NO-D trial (95% CI −24.3 to −7.5 mmHg; p=0.002) was diminished with PYRIDO (95% CI −21.0 to 1.6 mmHg; p=0.083), and 5 of the 10 participants had an increased DBP during HUT with PYRIDO. The difference in the BP response to HUT between the NO-D and the PYRIDO trial is presented (Figure 5). Although 3 individuals had higher BP during HUT following PYRIDO (≥ 10% compared to the NO-D response); 3 subjects had lower BP with PYRIDO (≤ 10% compared to the NO-D response). Demographic characteristics did not distinguish responders from non-responders; however, supine HR was significantly reduced in those that had an increase in orthostatic BP following PYRIDO administration compared to those who did not (49±4 vs. 59±9 bpm, respectively; p=0.009). Of note, the relationship between orthostatic change in SBP (mmHg) during HUT and supine HR approached statistical significance (r2=0.39; p=0.053)
Table 3.
Average Hemodynamics at 45° HUT
| Subject | HR | SBP | DBP | |||
|---|---|---|---|---|---|---|
| NO-D | PYRIDO | NO-D | PYRIDO | NO-D | PYRIDO | |
| K01 | 80 | 72 | 66 | 77 | 52 | 54 |
| K02 | 83 | 80 | 101 | 102 | 68 | 76 |
| K03 | 80 | 65 | 74 | 92 | 54 | 75 |
| K05 | 84 | 76 | 78 | 67 | 57 | 48 |
| K08 | 65 | 53 | 98 | 93 | 70 | 61 |
| K09 | 82 | 69 | 98 | 82 | 71 | 59 |
| K10 | 70 | 68 | 83 | 82 | 56 | 60 |
| K11 | 51 | 57 | 95 | 83 | 64 | 63 |
| K12 | 51 | 45 | 102 | 134 | 69 | 85 |
| K13 | 75 | 81 | 90 | 86 | 65 | 63 |
| mean±std | 72±13 | 66±12 * | 88±12 | 90±18 | 63±7 | 64±11 |
p<0.05 versus NO-D
Figure 3.
Depicts the hemodynamic responses to the progressive HUT maneuver during the NO-D (closed circles) and PYRIDO 60 mg (open squares) trials. Data reflect the average HR [A], SBP [B] and DBP [C] during the supine observation and at each angle of HUT (i.e., 15°, 25°, 35°, 45°). The main effect for drug and the interaction effect were not significant; however, the main effect for tilt angle was significant for HR (p<0.05) SBP (p<0.01) and DBP (p<0.05).
Figure 4.
Displays the change in hemodynamics from the BL to 45° HUT during the NO-D (closed circles) and PYRIDO 60 mg (open squares) trials. Data reflect the difference between the average HR [A], SBP [B] and DBP [C] at BL and 45°. The hemodynamic response to HUT was not different comparing the NO-D to the PYRIDO trial. * p<0.01 versus no change
Figure 5.
Displays the difference between the NO-D and PYRIDO trials for percent change in hemodynamics at 45° HUT for HR [closed circles], SBP [open squares] and DBP [closed triangles]. Dashed lines represent ±10% change in the hemodynamic parameters.
Symptoms of Orthostatic Intolerance
Responses to the symptoms questionnaire are presented (Table 4). The number and severity of symptoms reporting did not differ comparing the NO-D (20) to the PYRIDO (22) trial. However, 2 participants who were symptom limited and terminated the HUT test early during the NO-D trial were able to complete the maneuver following PYRIDO administration. Interestingly these 2 individuals had significant BP responses to PYRIDO (i.e., 17% and 25% increase in orthostatic SBP). Four of the subjects reported increased frequency of symptoms of OI with PYRIDO compared to NO-D, although all but one were able to complete the HUT maneuver.
Table 4.
Symptoms of Orthostatic Intolerance
| K01 | K02 | K03 | K05 | K08 | K09 | K10 | K11 | K12 | K13 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | NO | PY | |
| test termination (minutes) | 84 | 120 | 120 | 120 | 80 | 120 | 105 | 80 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 |
| light headedness | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| fatigue | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| blurred vision | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| dizziness | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| nausea | 0 | 1 | 0 | 2 | 0 | 2 | 0 | 3 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| faint | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| headache | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| yawning | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 4 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| sweating | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| salivation | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| disorientation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| very hot | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 12 | 4 | 0 | 4 | 1 | 3 | 3 | 6 | 0 | 0 | 4 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
Reporting of Side Effects
One participant complained of increased sweating and salivation following PYRIDO administration, another subject terminated the test earlier on the PYRIDO compared to the NO-D visit (80 vs. 105 minutes) due to overheating; however, this subject failed to complete the test on either study visit.
Discussion
We report, for the first time, the hemodynamic responses to HUT following PYRIDO administration in a cohort of individuals with SCI. Following PYRIDO administration, the findings suggest: 1) no evidence of significant elevation in supine BP; 2) equivocal findings on orthostatic BP responses and orthostatic tolerance and 3) minimal adverse side effects. Therefore, clinical use of AchI for treatment of asymptomatic OH may have utility in a subset of individuals with SCI.
Treatment of asymptomatic hypotension and OH in the SCI population is not a common clinical practice. We reported that the prevalence of hypotension recorded in the medical record was 39%,21 and documented hypotension over the course of a typical 24-hour day in 70% of subjects with tetraplegia.22 However, we found that the diagnosis of hypotension was less than 1% and treatment with prescription anti-hypotensive agents was negligible (3 of 1291 records: 0.2%) in veterans with tetraplegia.21 These findings most likely reflect the limited number of FDA approved agents available to treat hypotension and OH and a paucity of data supporting the safe and effective use of these medications in the SCI population.
Most individuals with chronic SCI remain asymptomatic during periods of significant hypotension, and therefore, do not raise clinical concern. However, in 1927, Norris described individuals with low BP as persons who lacked stamina, tired easily, complained of cold extremities, and showed an inability to do prolonged mental or physical work.23 Norris was quoted as saying; “they [hypotensive individuals] are not exactly ill; yet they are rarely well.”24 In the 1990s the British Medical Journal published a series of articles describing the association between low BP and mood disorders in the general population.8, 9, 25, 26 The findings indicate that individuals with chronic hypotension have significantly increased incidence of depression,8, 27–33 anxiety,28, 29 unexplained tiredness,8, 9 and poor perception of well-being compared to matched-normotensive controls.25 More recently we conducted focus group sessions in individuals with SCI and clinical care providers and found that both patients and clinicians were able to ascribe adverse effects of persistent asymptomatic hypotension on health related quality of life in those with SCI.34 In addition to these mood disorders asymptomatic hypotension is associated with cognitive deficits in the general population. In otherwise healthy non-SCI individuals, hypotension has been associated with slowed cognitive speed35, fewer word recall36, decreased accuracy of response5, limited attention36, prolonged reaction times5, 6, 35 and reduced memory and concentration capacity5, 6 compared to normotensive controls. We previously reported significantly reduced memory and marginally reduced attention processing in hypotensive individuals with SCI compared to a normotensive SCI cohort,10 and speculate that this finding may relate to sub-clinical cerebral hypoperfusion.37, 38 These data strongly suggest that chronic asymptomatic hypotension is not a benign condition and, therefore, treatment options should be considered.
We believe however, that before routine clinical treatment of asymptomatic hypotension is considered a priority in the SCI population data are required to confirm the safe and effective use of a variety of agents with different mechanisms of action. Reports on the use of AchI to treat symptomatic OH in persons with neurogenic autonomic dysfunction15, 16, 18 presents a novel therapeutic approach, which has the potential to be effective without significant adverse effects.
Selective increase in orthostatic BP, without concomitant increase in supine BP, is an important consideration in treatment of OH in the SCI population. There was no significant increase in supine systolic or diastolic BP and supine BP remained below the lower limit of normotension (i.e., 120/80 mmHg) in all subjects tested following PYRIDO administration. However, the orthostatic fall in BP was attenuated with PYRIDO compared to NO-D. Importantly, individual responses to PYRIDO varied among our subjects. In fact, following PYRIDO 5 subjects had an increase in either SBP or DBP during HUT and 5 had a decrease in orthostatic BP compared to the NO-D trial. Because Ach is the pre-synaptic neurotransmitter of the sympathetic nervous system, we hypothesized that individuals with an incomplete autonomic lesion would respond with improved orthostatic BP responses to AchI. Although responders could not be distinguished from the non-responders by any demographic parameter, including AIS classification of motor and sensory impairment, we were unable to assess the completeness of the injury to the autonomic nervous system. That said supine HR was significantly reduced in the responders compared to the non-responders. This finding is intriguing and suggests that individuals with resting bradycardia may have increased pre-synaptic Ach concentrations and thus, may benefit from AchI therapy in treatment of hypotension and OH. However, this finding should be substantiated in a larger sample of subjects with SCI.
Neither the frequency nor intensity of reporting symptoms of OI were changed following PYRIDO administration compared to the NO-D trial. In fact, most study participants who reported symptoms on the NO-D visit also reported symptoms during the PYRIDO visit and 4 subjects actually increased symptoms reporting following PYRIDO. This finding may be attributed to the order of testing, which was not randomized, and a heightened awareness of subjective symptomology on the second visit, because there was no association between the BP response to the HUT maneuver and symptoms reporting on either the NO-D or the PYRIDO visits. Although the data do not confirm efficacy, 2 of the 3 subjects who were symptom limited during the NO-D trial and terminated the orthostatic maneuver early, were able to complete the full test following PYRIDO administration. The number and severity of AEs reported in this small cohort of subjects with SCI was minimal.
Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system and therefore AchI has the potential to enhance vagal control of the heart and induce bradycardia. Although PYRIDO did not significantly reduce supine HR, there was a significant attenuation in the HR response to HUT. This finding corroborates an earlier report on the orthostatic HR response to PYRIDO in models of neurogenic OH18 and suggests that the impact of AchI is rate dependent. Thus, it appears that AchI exerts a direct effect on muscarinic synapses, which supersedes indirect ganglionic potentiation of sympathetic outflow to the heart.
Study Limitations
We did not evaluate the impact of AchI on BP responses during autonomic dysreflexia (AD), which is defined as an increase in BP (i.e., ≥ 20/10 mmHg) that may or may not be associated with symptoms including pounding headache, profuse sweating and piloerection above the level of lesion.39 Because AD arises from unrestrained post-ganglionic sympathetic outpouring of norepinephrine, the use of AchI may augment the BP response by increasing pre-synaptic neurotransmitter signaling. The use of HUT as an orthostatic provocation does not reflect a clinically relevant orthostatic position, and data on prolonged seated hemodynamic responses to PYRIDO should be studied. The study was designed with safety as a priority and aimed to determine proof of concept; as such the investigation was un-blinded, non-randomized and lacked placebo control, which limits interpretation of the data. Finally, the heterogeneity in BP responses to PYRIDO, the relatively small sample size and the predominantly male sample, make extrapolation of these findings to the general SCI population speculative at best.
Conclusion
These preliminary findings suggest that PYRIDO may ameliorate the orthostatic fall in BP in select individuals with SCI. While the data on efficacy were not astounding, this agent appears to be safe; without significant increases in supine BP or AE reporting. The use of AchI in the management of daily seated hypotension and the effects on cerebral blood flow should be studied in a larger sample of hypotensive subject with SCI.
Supplementary Material
Acknowledgments
Grant Support: This research was supported by the Veterans Affairs Rehabilitation Research and Development Service (grant # B9212C).
Disclosure: We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated AND, if applicable, we certify that all financial and material support for this research (eg, NIH or NHS grants) and work are clearly identified in the title page of the manuscript.
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