Respiratory Training Improves Blood Pressure Regulation in Individuals With Chronic Spinal Cord Injury

Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2016;-:-------

ORIGINAL RESEARCH

Respiratory Training Improves Blood Pressure Regulation in Individuals With Chronic Spinal Cord Injury Sevda C. Aslan, PhD,a David C. Randall, PhD,b Andrei V. Krassioukov, MD, PhD,c,d,e Aaron Phillips, PhD,c,d,e Alexander V. Ovechkin, MD, PhDa From the aDepartment of Neurological Surgery, University of Louisville, Louisville, Kentucky; bDepartment of Physiology, University of Kentucky, Lexington, Kentucky; cExperimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada; d International Collaboration on Repair Discoveries (ICORD), Department of Medicine, Division of Physical Medicine and Rehabilitation, University of British Columbia, Vancouver, British Columbia, Canada; and eGF Strong Rehabilitation Centre, Vancouver Coastal Health, Vancouver, British Columbia, Canada.

Abstract Objective: To investigate the effects of respiratory motor training (RMT) on pulmonary function and orthostatic stressemediated cardiovascular and autonomic responses in individuals with chronic spinal cord injury (SCI). Design: Before-after intervention case-controlled clinical study. Setting: SCI research center and outpatient rehabilitation unit. Participants: A sample of (NZ21) individuals with chronic SCI ranging from C3 to T2 diagnosed with orthostatic hypotension (OH) (nZ11) and healthy, noninjured controls (nZ10). Interventions: A total of 21
2 sessions of pressure threshold inspiratory-expiratory RMT performed 5d/wk during a 1-month period. Main Outcome Measures: Standard pulmonary function test: forced vital capacity, forced expiratory volume in one second, maximal inspiratory pressure, maximal expiratory pressure, beat-to-beat arterial blood pressure, heart rate, and respiratory rate were acquired during the orthostatic situp stress test before and after the RMT program. Results: Completion of RMT intervention abolished OH in 7 of 11 individuals. Forced vital capacity, low-frequency component of power spectral density of blood pressure and heart rate oscillations, baroreflex effectiveness, and cross-correlations between blood pressure, heart rate, and respiratory rate during the orthostatic challenge were significantly improved, approaching levels observed in noninjured individuals. These findings indicate increased sympathetic activation and baroreflex effectiveness in association with improved respiratory-cardiovascular interactions in response to the sudden decrease in blood pressure. Conclusions: Respiratory training increases respiratory capacity and improves orthostatic stressemediated respiratory, cardiovascular, and autonomic responses, suggesting that this intervention can be an efficacious therapy for managing OH after SCI. Archives of Physical Medicine and Rehabilitation 2016;-:------ª 2016 by the American Congress of Rehabilitation Medicine

Approximately 60% of people with chronic spinal cord injury (SCI) exhibit symptoms of orthostatic hypotension (OH),1,2 which is associated with an inability to participate in Supported by the Kentucky Spinal Cord and Head Injury Research Trust (grant no. 9-10A), the Christopher and Dana Reeve Foundation (grant no. OA2-0802), the Craig H. Neilsen Foundation (grant no. 1000056824), and the National Institutes of Health (grant nos. R01HL103750 and P30GM103507). Disclosures: none.

activities of daily life3,4 and rehabilitation5,6 with an increased risk of stroke7 and cognitive dysfunctions.8,9 Respiration affects hemodynamics by supporting cardiac output10-12 and by participating in autonomic regulation of heart rate and blood pressure via baroreflex modulations.13-16 These respiratory-cardiovascular interactions17,18 are compromised after SCI.1,11,19-22 Currently, there is no standardized management strategy for blood pressure dysregulation after SCI.5,23,24 Respiratory

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S.C. Aslan et al Table 1

Characteristics of patients with SCI and NI individuals Participant

SCI (nZ11)

NI (nZ10)

B06 A38 A43 B11 B13 B17 C30 B19 C26 A58 C34 Mean
SD Mean
SD

Age (y)

Sex

Height (cm)

Weight (kg)

Level of SCI

AIS Category

Time After SCI (mo)

41 37 30 23 31 42 18 39 33 40 20 32
9 33
10

F F M M M M F M M M M 3 F and 8 M 2 F and 8 M

170 175 188 173 180 191 168 188 183 178 193 181
8 173
10

56 51 95 84 97 99 42 82 75 104 64 77
21 75
12

C4 C4 T2 C5 C7 C5 C4 C6 C7 C3 C4 NA NA

B A A B C B C B C A C NA NA

72 252 11 96 36 15 12 7 6 22 55 53
72 NA

NOTE. AIS categories A and B represent motor complete and C and D represent motor incomplete SCI. Abbreviations: AIS, American Spinal Cord Injury Association Impairment Scale; F, female; M, male; NA, not available; NI, noninjured.

training is a widely used technique in clinical practice, but the consistent benefits of this intervention are somewhat contentious because of poor understanding of the underlying therapeutic mechanisms.25-27 The objective of this study was to investigate the effects of pressure threshold inspiratory-expiratory training, termed here as a respiratory motor training (RMT), on pulmonary function and orthostatic stressemediated cardiovascular and autonomic responses. It was hypothesized that RMT improves baroreflex responses and respiratory-cardiovascular interactions in patients with SCI-induced OH. This technique has never been evaluated for its ability to improve blood pressure regulation in individuals with SCI.

Clinical assessment Eleven participants with SCI and 10 physically (age, sex, height, weight) matched noninjured controls participated in this study. The neurological level and completeness of the spinal cord lesion were determined using the American Spinal Cord Injury Association Impairment Scale.28 Seven participants were classified as having motor complete SCI, and 4 participants were diagnosed with motor incomplete SCI ranging from C3 to T2 (table 1).

Pulmonary function test

Methods Material Informed consent was obtained as approved by the Institutional Review Board for Human Research of the University of Louisville according to the inclusion criteria: at least 18 years of age; a minimum of 6 months since SCI; no ventilatory dependence; and OH defined as a decrease in arterial systolic blood pressure (SBP) of at least 20mmHg or a decrease in diastolic blood pressure (DBP) of at least 10mmHg or more upon changing from the supine position to the upright posture.2 Individuals with painful musculoskeletal dysfunction; unhealed fracture; contractures; clinically significant depression or ongoing drug abuse; cardiovascular, respiratory, bladder, or renal diseases unrelated to SCI; human immunodeficiency virus/AIDS-related illness; anemia, hypovolemia, pregnancy, endocrine, and neurological diseases were excluded from this study.

List of abbreviations: DBP HF LF OH PSD RMT SBP SCI

diastolic blood pressure high-frequency low-frequency orthostatic hypotension power spectral density respiratory motor training systolic blood pressure spinal cord injury

Standard spirometrical measurements (forced vital capacity, forced expiratory volume in one second, maximal inspiratory pressure, maximal expiratory pressure)13,29,30 were assessed as described previously.31

Orthostatic stress test A sit-up test with continuous recordings of blood pressure, heart rate, and respiratory rate was used for the diagnose of OH and for beat-tobeat data acquisition at 1000Hz, and those recordings were analyzed using MATLAB software.32,33,a SBP and DBP were acquired from a finger cuff using Portapres-2b and ML880 PowerLab 16/30c systems. Brachial blood pressure measurements using a Dinamap V100d were acquired at the beginning and end of each position phase to calibrate the beat-to-beat blood pressure values. The ML132 3-lead II electrodesc and Inductotrace system bandse were used to record electrocardiograms and to assess the respiratory rate.32 Hemodynamic variables (presented as mean
SD) were calculated for 5-minute intervals from 15 minutes of the supine position, 1-minute intervals from the first 3 minutes of sitting, and 3-minute intervals from 3 to 15 minutes of the sitting position. Power spectral density (PSD) of heart rate, PSD of blood pressure, and respiratory rate were calculated for 5-minute intervals in both positions. Each interval was linearly detrended, and power spectral density was estimated using Welch’s averaged periodogram method (500-point windows with 50% overlapping segments). Mean power spectral density was calculated for low-frequency (LF) (.04e.15Hz) and high-frequency (HF) (.15e.40Hz) regions www.archives-pmr.org

Respiration and orthostatic hypotension after spinal cord injury Table 2

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Summary of pulmonary function test values obtained before and after RMT FVC (% Predicted)

FEV1 (% Predicted)

PImax (cmH2O)

PEmax (cmH2O)

Participant (nZ11)

Before RMT

After RMT

Before RMT

After RMT

Before RMT

After RMT

Before RMT

After RMT

B06 (C4B) A38 (C4A) A43 (T2A) B11 (C5B) B13 (C7C) B17 (C5B) C30 (C4C) B19 (C6B) C26 (C7C) A58 (C4A) C34 (C7C) Mean
SD

46 51 52 47 77 70 41 70 60 65 37 56
13

57 44 72 56 67 74 69 81 76 60 40 63
13*

38 47 55 34 74 58 45 66 67 53 29 51
14

40 49 67 38 66 68 46 77 76 55 28 55
16

32 20 110 93 103 61 46 54 101 20 40 62
34

41 25 127 114 101 60 46 52 103 79 42 72
35

25 23 56 64 64 30 27 35 70 21 34 41
19

26 28 56 69 50 32 26 47 77 29 41 44
18

NOTE. Participant ID codes include the American Spinal Cord Injury Association Impairment Scale level and category of each subject. FVC was significantly increased after RMT. Abbreviations: FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PEmax, maximal expiratory pressure; PImax, maximal inspiratory pressure. * P<.05.

using trapezoidal integration over the specified frequency range.34-36 Baroreflex effectiveness index (%) and baroreflex sensitivity (ms/ mmHg) were determined using the standard approach.35 The coefficients for cross-correlations between SBP and heart rate oscillations in LF/HF regions and those between heart rate and respiratory rate oscillations in HF regions were calculated as described previously.32

Results

Respiratory motor training

Pulmonary function test

Research participants were seated in their personal wheelchair during each training session with an w45 head-up tilt. A threshold positive expiratory pressure device and an inspiratory muscle trainerf were assembled using a 3-way valve system (Airlife 001504g) with a flanged mouthpiece. Patients performed 6 work sets, 5 minutes in duration, separated by rest intervals lasting 3 minutes. Individuals were trained 5d/wk for 45min/d during 1 month. The training was initiated at intensity equal to 20% of their individual maximal inspiratory pressure and maximal expiratory pressure, with progressive increases as tolerated up to 40% of these values at the end of the training program.37-39 No adverse events related to significant changes in blood pressure or symptoms of intolerance were observed during training sessions.

The pulmonary function test outcomes were increased after RMT as compared with the pretraining levels, reaching significance in forced vital capacity values (P<.05) (table 2).

Statistical analysis The study sample size was estimated using the G*Power tool (version 3.1.9.2),40,h with the level of significance (a) and statistical power (1b) set at .05 and .80, respectively. The effect size was estimated using Cohen’s d calculations for paired samples. Comparisons between pulmonary function test unidentified data sets obtained before and after the RMT program were made using the paired 2-tailed t test. Unidentified hemodynamic data were fit with a linear mixed effects model and reported as mean
SD. Research group, position (supine or sitting), and an interaction term were the fixed factors in the model. A random intercept was included to account for the added covariation of repeated measurements. Comparisons between groups and positions were www.archives-pmr.org

derived from the mixed model fit through standard F tests of linear contrasts of the model coefficients. All hypothesis tests were conducted at P<.05, with a set at .05. All analyses were performed using the open-source R software 3.0.2 package.i

Table 3 Supine to-seated change in SBP and DBP during the orthostatic stress test SBP/DBP (mmHg) From 0 to 3min of the Sitting Position

From 3 to 10min of the Sitting Position

Participant

Before RMT

After RMT

Before RMT

After RMT

B06 (C4B) A38 (C4A) A43 (T2A) B11 (C5B) B13 (C7C) B17 (C5B) C30 (C4C) B19 (C6B) C26 (C7C) A58 (C3A) C34 (C4C)

24/9* þ10/þ7y 20/4* 26/9* 16/5y 31/17* 29/11* 21/þ4* 8/5y 2/þ5y 23/19*

36/26* þ5/þ1y 17/1y 8/þ14y 1/þ12y 3/0y 11/þ12y 3/þ1y 10/þ6y 8/3y 24/24*

39/17* 20/11* 20/4*,z 31/4* 34/11* 46/25* 25/8* 29/þ1* 36/19* 27/4* 36/25*

40/28* 5/5y 14/þ4y 11/þ12y 15/þ5y 17/9y 19/1y 12/6y 34/13* 34/13* 36/27*

NOTE. Participant ID codes include the American Spinal Cord Injury Association Impairment Scale level and category of each subject. After RMT, considerable drop in SBP (-20mmHg) or DBP (-10mmHg) characterizing OH (*) is not seen (y) in 7 of 11 participants. z This participant could not complete the sitting phase.

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Orthostatic stress test Before training, OH was diagnosed in all 11 individuals with SCI: in 7 of them, the “orthostatic” drop in blood pressure was detected within 3 minutes and in the other 4, within 10 minutes of assuming the sitting position. After RMT, this orthostatic drop was seen in only 4 participants (in 2 individuals within 3min and in the other 2 within 10min of the onset of the sitting phase). One individual (A43), before RMT, became presyncopal after only 5 minutes of the orthostatic challenge, which required protocol cessation; after RMT, however, he could complete the test (table 3). Figure 1 shows blood pressure responses in 1 individual (A38) before and after RMT, whereas table 3 summarizes the effects of RMT on blood pressure across all individuals. In the SCI group, before RMT, both SBP and DBP decreased continuously within the first 6 minutes of assuming the sitting position and stabilized at lowered levels from 6 to 15 minutes. In contrast, upon completion of RMT, both pressures decreased for the first 3 minutes and then remained constant from 3 to 15 minutes of the sitting position (figs 2A and B). Compared to pretraining baseline measurements, these supine-to-seated decreases in blood pressure were significantly smaller after RMT (figs 3A and B). Heart rate responses in all groups in both positions were similar: stable during the supine position and increased significantly in the sitting position from 60
10 to 67
8beats/min (PZ.0006) in the noninjured group, from 58
6 to 73
16beats/ min (PZ.0002) in the SCI group before RMT, and from 58
8 to 77
15beats/min (PZ.006) in the SCI group after RMT. Before RMT, baroreflex effectiveness remained significantly decreased compared with that during supine baseline measurements throughout the entire 15-minute sitting period. Conversely,

Fig 1 Dynamics (mean
SD/min) of SBP and DBP (black) and heart rate (gray) during the sit-up orthostatic stress test in an individual with C4 American Spinal Cord Injury Association Impairment ScaleeA SCI (A38) before (A) and after (B) RMT. Note that considerable drop in SBP (20mmHg or more) and DBP (10mmHg or more) characterizing OH before RMT is not seen after RMT. Also note the stability of the blood pressure and heart rate response achieved after RMT.

S.C. Aslan et al this significant decrease was seen only during the initial (0- to 5minute) period when assessed after RMT (fig 4A). Baroreflex sensitivity in the sitting position was significantly lower than that during supine baseline in all participants from noninjured and SCI groups before and after RMT (fig 4B). The group mean of the LF component of PSD of heart rate during supine baseline was not different across the groups (fig 5A). Compared to baseline, this index increased significantly during 10 to 15 minutes of the sitting position in the noninjured group and decreased significantly during 5 to 15 minutes of the sitting position in the SCI group when assessed before RMT. This significant decrease in the index in the upright position was not seen after RMT (see fig 5A). The group mean of the LF component of PSD of SBP (fig 5B) and DBP (fig 5C) at rest tended to be lower in the SCI group than in the noninjured group both before and after RMT, though neither difference reached significance. Both indices increased significantly in response to orthostatic stress in noninjured individuals. Compared to baseline, the LF component of PSD of SBP increased significantly during 0 to 5 minutes of the sitting position in individuals with SCI when assessed both before and after RMT. This increase, however, was elevated versus the nadir during the remainder of the sitting period only after RMT (see fig 5B). The LF component of PSD of DBP in the SCI group did not show any significant change in the sitting phase when recorded both before and after RMT (see fig 5C). In the supine position, the HF component of PSD of heart rate was not significantly different in noninjured (282
194beats/min) and SCI (202
119beats/min) groups. These values were slightly decreased to 263
204beats/min in noninjured individuals. In contrast, there was a significant decrease to 49
45beats/min in the SCI group during the last 5 minutes of the sitting position. After RMT, this pattern was not changed, showing a significant decrease from 183
99beats/min in the supine position to 60
49beats/min during the last 5 minutes of the sitting position. Both the LF and HF components of the cross-correlation between blood pressure and heart rate were examined. There were no significant differences in the supine position between any group in the mean magnitude of the negative component (eg, a decrease in blood pressure associated with an increase in heart rate, and vice versa) of the LF cross-correlation. This measure was increased significantly during 10 to 15 minutes of the sitting position in the noninjured group. In the SCI group, this index decreased significantly within 5 minutes of assuming the sitting position before and after RMT. This index remained significantly lower than the baseline value in participants with SCI before RMT, whereas after RMT it increased back toward its baseline value during the remainder of the sitting period. Figure 6 (where red indicates a strong positive cross-correlation and blue indicates a strong negative cross-correlation) provides a visual summary of this dynamic process within the LF range. Cross-correlation coefficients between heart rate and SBP in HF regions were similar in all groups during the last 5 minutes of supine and sitting positions as well as before and after RMT in the SCI group (noninjured group: .70
.10 vs .76
.10; SCI group: .72
.10 vs .67
.20 before RMT and .71
.10 vs .68
.20 after RMT). Group mean respiratory rate oscillations (Hz) were similar in noninjured and SCI groups (noninjured group: .23
.08 and .23
.05; SCI group: .22
.06 and .25
.05 before training and .25
.07 and .26
.08 after training in supine and sitting positions, respectively). The noninjured group showed positive crosscorrelation with almost zero time delay between respiratory rate oscillations and heart rate fluctuations throughout the test with www.archives-pmr.org

Respiration and orthostatic hypotension after spinal cord injury

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Fig 2 Dynamics (mean
SD) of SBP (A) and DBP (B) during the orthostatic stress test in NI and SCI groups before and after RMT. Note a significant (P<.05) increase in both SBP and DBP in NI individuals (*) and a significant decrease in SBP and DBP in individuals with SCI in the upright position compared to the values obtained in the supine position before RMT (y) and SBP after RMT (). Also note positive dynamics of both SBP and DBP in participants with SCI after RMT and no significant difference compared to supine baseline measurements in DBP after RMT. Abbreviation: NI, noninjured.

increased intensity from 5 to 15 minutes of the sitting position. In the SCI group, this correlation at rest was negative with no postRMT change; however, after RMT, in the sitting position it was positive with significant improvement toward the normal values observed in noninjured individuals (figs 7A and B).

Discussion In the present study, it is reported that RMT reduces the severity of OH in individuals with chronic SCI. The findings indicate that this effect is associated with significantly increased respiratory capacity, improved baroreflex-mediated autonomic activation, and better synchronized cardiorespiratory coupling interactions in response to assuming an upright posture. The most clinically relevant finding is that RMT resulted in a remarkable improvement in the ability to maintain physiological levels of the blood pressure in response to orthostatic stress. The ability to assume an upright posture without an orthostatic drop in blood pressure was acquired in 64% of participants with SCI. This finding seems particularly remarkable given that these individuals

had not established an effective orthostatic response in the average of 53
72 months after SCI, indicating that RMT can be used to shorten the time between injury and the initial steps leading to eventual resumption of a more stable lifestyle. The results of this study have indicated increase in post-RMT respiratory performance associated with improved respiratory motor function (see table 2). This finding is consistent with reports of others suggesting that respiratory exercise is effective for improving respiratory function in individuals with SCI during acute41 and chronic42-47 SCI as well as in patients with other disorders.48-50 However, the approach of reciprocal inspiratoryexpiratory training with adjustable load has never been used previously in the population with SCI. The term respiratory motor training was chosen in lieu of the more commonly used respiratory muscle training to reflect the intent not only to affect the respiratory muscles but also to intervene the respiratory neuromuscular motor control and to challenge the respiratorycardiovascular coupling interactions during cycles of intrathoracic pressure fluctuations that is accompanied by blood pressure oscillations. These oscillations are thought to potentially “train” the baroreflex and autonomic networks to respond to fluctuations

Fig 3 Change (mean
SD) in SBP (A) and DBP (B) during the orthostatic stress test in the sitting position from supine baseline in the SCI group before and after RMT. Note that RMT significantly (P<.05) mitigated the decrease in both SBP and DBP observed before RMT ().

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S.C. Aslan et al

Fig 4 BEI (A) and BS (B) during the orthostatic stress test in the NI group and in the SCI group before and after RMT (mean
SD/5min). Note a significant (P<.05) supine-to-seated decrease in BEI in individuals with SCI before RMT (y) and that this decrease was not significant during the late sitting phase after RMT (). Also note the positive trend toward the NI control curve that is observed after RMT in both BEI and BS in the sitting position. Abbreviations: BEI, baroreflex effectiveness index; BS, baroreflex sensitivity; NI, noninjured.

in blood pressure in a normal physiological manner. Furthermore, stiffening of the central arteries is responsible for the majority of cardiovagal baroreflex decline after high level SCI.51 By imposing healthy sheer stress on arteries with embedded baroreceptors, the oscillations in blood pressure during the RMT session may improve the arterial stiffening and increase baroreceptors’ elasticity. The reported data indicate that the diagnosis of OH by using the sit-up orthostatic stress test33,52 in individuals with SCI requires up to a 15-minute long observation period in the upright sitting position (see table 3). Documented in 54% of the population without SCI, this delayed response was associated with milder abnormalities of sympathetic adrenergic function that progressed over time.53-55 After SCI, this phenomenon may be aggravated by functional deconditioning and neurodegeneration. Interestingly, the results of this study indicate that all post-RMT improvements related to cardiovascular and autonomic function were attributable to the responses that occurred predominately during second half of the sitting phase of the orthostatic stress test (see table 3 and figs 1-7).

A number of observations jointly point toward the conclusion that RMT improved baroreflex responses via augmented autonomic responses. First, baroreflex effectiveness and sensitivity were improved after RMT, indicating better coordination between beat-to-beat blood pressure and heart rate changes mediated by the cardiovagal reflex (see figs 4A and B). Because the cardiovagal control is intact after SCI,56-58 this improvement can be associated with decreased orthostatic stressemediated vagal withdrawal and better cardiopulmonary coupling that heavily depends on parasympathetic control.59 Second, the LF component of power spectral density of heart rate, primarily indicating the cardiac sympathetic activity, as well as the LF component of power spectral density of arterial blood pressure, a marker of efficacious sympathetic vasomotor outflow, decreased significantly after assuming the upright posture in the participants before RMT, but were maintained after training (see fig 5). The most conservative interpretation of the increase in the negative LF cross-correlation after RMT (see fig 6) is that the training somehow helped reenable that component of the baroreflex dependent on sympathetic innervation. RMT may well have exerted its influence via

Fig 5 LF PSD of HR (A); SBP (B) and DBP (C) oscillations during the orthostatic stress test in the NI group and in the SCI group before and after RMT (mean
SD/5min). Note that compared to supine baseline, all outcomes in NI individuals were significantly increased (P<.05) in the sitting position (*) in contrast to individuals with SCI. Also note significantly decreased LF PSD of HR in individuals with SCI in the sitting position before RMT (y) but no such significant difference in this outcome after RMT. In contrast to pretraining levels, LF PSD of SBP was significantly higher throughout the sitting period after RMT (). Abbreviations: HR, heart rate; LF PSD, low-frequency component of power spectral density; NI, noninjured.

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Respiration and orthostatic hypotension after spinal cord injury

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Fig 6 Distribution (A) and magnitude (B) of the LF (.04e.15Hz) negative cross-correlation between HR and SBP during the orthostatic stress test in the NI group and in the SCI group before and after RMT (mean
SD/5min). In panel A, the lag is given on the vertical axes, where negative lag refers to changes in SBP-leading HR and positive lags refers to SBP-lagging HR. The magnitude of the correlation is indicated by the color density according to the scale presented in vertical bars on the right. The strong blue band around 2.5s in the NI group represents responses characteristic of baroreflex function. Note that compared to supine baseline, the negative magnitude was significantly increased (P<.05) in the sitting position in individuals with NI (*) relative to SCI individuals. Also note its significant decrease in individuals with SCI in the sitting position before RMT (y) and no significant difference in this outcome after RMT () that was associated with a positive change in distribution. Abbreviations: HR, heart rate; NI, noninjured.

functional improvement in both branches of the autonomic nervous system. We speculate that such enhancement may be via the improved balance between intact vagal control and injured sympathetic pathways at the fringe of the lesion that are not functioning for a time postinjury, but which may ultimately regain at least minimal function.60 Inspiration and expiration have mechanical sequelae with significant hydraulic effects.12,61-64 Even during a transition to an upright posture an increased intensity of respiratory movements secondary to RMT might be expected to defend, or even increase, the pressure gradient for venous return and, thereby, increasing the

cardiac output.11 Patients with OH65 and individuals with tetraplegia can prevent the orthostatic events by voluntarily increased breathing effort during transferring from the supine to the sitting position.66 In the present study, RMT significantly improved synchronization between heart rate and respiration (see fig 7), which may indicate more effective respiratory pumping to fight the orthostatic drop in blood pressure. Respiratory training protocols can modulate baroreflex responses through the increase in vagal activity and reduction in sympathetic activity in hypertensive individuals67,68 and rats.69 In the present study, RMT is associated with significantly increased

Fig 7 Distribution (A) and magnitude (B) of the HF (.15.40Hz) negative cross-correlation between HR and respiratory chest kinematics during the orthostatic stress test in the NI group and in the SCI group before and after RMT (mean
SD/5min). The lag is given on the vertical axes, where negative lag refers to respiratory rateeleading HR and positive lag refers to respiratory rateelagging HR. The magnitude of the correlation is indicated by the color density according to the scale presented in vertical bars on the right. The red or blue bands around 0s represent positive (red) or negative (blue) correlation between HR and chest movements (positive correlation represents increase in HR during inspiration and decrease in HR during expiration). Note significantly (P<.05) improved post-RMT correlation during the orthostatic stress test in the sitting position compared to the pre-RMT levels (). Abbreviations: HR, heart rate; NI, noninjured.

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S.C. Aslan et al

sympathetic activation in response to sudden decrease in blood pressure. Obviously, these findings are attributable to the fundamental differences in pathophysiological nature of the autonomic and blood pressure abnormalities observed in SCI, hypertension, and heart failure. However, the fact that a similar therapeutic approach to manage these different diseases can produce the specifically desirable effects is intriguing and requires further investigation.

Acknowledgments We express our deep appreciation to Steven R. Williams, MD, Michael D. Stillman, MD, and Carie Z. Tolfo, PT, DPT, for the clinical support of this study. We also thank Edward H. Brown Jr, MS, MBA, Manpreet C. Chopra, BS, Bonnie Ditterline, PhD, Goutam Singh, MS, and Douglas J. Lorenz, PhD, for their contribution to research management, data acquisition, data processing, and statistical support.

Study limitations We did not assess the severity of injury to the spinal autonomic pathways that could affect the outcomes of RMT effectiveness.33,70 The study was also limited by group heterogeneity and relatively small sample size. It is always challenging to form demographically and clinically homogeneous groups from a highly diverse but limited population with SCI. In addition, it was not feasible to elucidate the impact of combinatory effects of neurological, pulmonary, and cardiovascular factors.

Conclusions The results of this study indicate that RMT improves pulmonary function and orthostatic stressemediated respiratory, cardiovascular, and autonomic responses and suggest that this intervention can be an efficacious therapy for managing OH after SCI. These findings provide some insight into the mechanisms of these benefits, which can be associated with awakened autonomic networks, harnessing respiratory pump, and improved cardiovascular baroreflex function. These results highlight the need for future investigations into the links between pulmonary and cardiovascular interactions.

Suppliers a. b. c. d. e. f. g. h. i.

The MathWorks. Finapres Medical System B.V. ADInstruments. GE Medical Systems. Ambulatory Monitoring Inc. Respironics Inc. Allegiance Healthcare Corp. Universities of Dusseldorf, Kiel, and Mannheim. R Development Core Team.

Keywords Autonomic nervous system; Blood pressure; Breathing exercises; Hypotension, orthostatic; Rehabilitation; Respiration; Spinal cord injuries

Corresponding author Alexander V. Ovechkin, MD, PhD, Department of Neurological Surgery, University of Louisville, 220 Abraham Flexner Way, Suite 1520, Louisville, KY 40202. E-mail address: alexander. [email protected].

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