Spinal cord injury

Study objectives: Previous spirometric findings among subjects with chronic tetraplegia that reduction in FE[V.sub.1] and maximal forced expiratory flow, mid-expiratory phase (FE[F.sub.25-75%]) correlated with airway hyperresponsiveness to histamine, and that many of these subjects exhibited significant bronchodilator responsiveness, suggested that baseline airway caliber was low in this population. To better evaluate airway dynamics in patients with spinal cord injury, we used body plethysmography to determine specific airway conductance (sGaw), a less effortdependent and more reflective surrogate marker of airway caliber. Design: Cohort study.

Setting: Veterans Affairs medical center.

Participants: Thirty clinically stable subjects with chronic spinal cord injury, inducting 15 subjects with tetraplegia (injury at C4-C7) and 15 subjects with low paraplegia (injury below T7), participated in the study. Fifteen able-bodied individuals served as a control group.

Interventions: Subjects underwent baseline assessment of spirometric and body plethysmographic parameters. Repeat measurements were performed among subjects with tetraplegia and paraplegia before and 30 min after receiving aerosolized ipratropium bromide (2.5 mL 0.02% solution; 12 subjects) or normal saline solution (2.5 mL; 6 subjects).

Measurements and results: We found that subjects with tetraplegia had significantly reduced mean values for sGaw (0.16 cm [H.sub.2]O/s), total lung capacity, FVC, FE[V.sub.1], and FE[F.sub.25-75%] compared to subjects in the other two groups. Subjects with tetraplegia who received ipratropium bromide experienced significant increases in sGaw (135%), FE[V.sub.1] (12%; 260 mL), and FE[F.sub.25-75%] (27%). Significant, though far smaller, increases in sGaw (19%) were found among subjects with paraplegia. No discernable change in any pulmonary function parameter was found following the administration of normal saline solution.

Conclusions: Subjects with tetraplegia, as opposed to those with low paraplegia, have reduced baseline airway caliber due to heightened vagomotor airway tone, which we hypothesize is the result of the interruption of sympathetic innervation to the lungs, and/or from low circulating epinephrine levels. (CHEST 2005; 127:149-155)

Key words: airway resistance; bronchodilator agents; spinal cord diseases; tetraplegia; whole-body plethysmography

Abbreviations: ERV = expiratory reserve volume; FE[F.sub.25-75%] = maximal mid-expiratory flow; FRC = functional residual capacity; Gaw = airway conductance; Pst(L) = lung elastic recoil pressure; Raw = airway resistance; RV = residual volume; sGaw = specific airway conductance; TLC = total lung capacity; Vtg = thoracic gas volume

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A significant number of spontaneously breathing subjects with chronic tetraplegia, but not those with paraplegia, exhibit nonspecific airway hyperreactivity (1-5) and bronchodilator responsiveness (6,7) following the inhalation of bronchomodulating agents. These findings, which appear to be independent of the completeness of injury and smoking history, imply the presence of a physiology unique to tetraplegia. Subsequent findings that lower values for the natural logarithmic transformation of the provocative concentration of histamine causing a 20% fall in FE[V.sub.1] correlated with parallel reductions in surrogate spirometric indexes of resting airway caliber (ie, FE[V.sub.1], maximal forced expiratory flow, mid-expiratory phase [FE[F.sub.25-75%], and the FE[F.sub.25-75%]/FVC ratio) suggested that airway hyperreactivity was related to the reduction in baseline airway caliber. (8) Since resistance to flow in conducting airways is inversely related to the fourth power of the radius, already constricted airways could manifest greater responses to bronchomodulating agents compared to the same degree of dilatation or constriction elicited in airways having normal caliber. (9) Tetraplegia is distinguished from low paraplegia by the interruption of sympathetic innervation to the lungs arising from the upper six thoracic segments of the spinal cord and/or from low circulating epinephrine levels resulting from adrenal gland denervation. Both of these processes could lead to overriding vagal airway tone.

Among subjects with tetraplegia, the degree to which airway caliber is reflected by spirometric indexes is lessened if during repeated spirometric maneuvers decreased force generation results in suboptimal expiratory efforts in which flow limitation is not reached. (10) Airway caliber might therefore be more accurately assessed by the use of whole-body plethysmography to measure specific airway conductance (sGaw), which is also a sensitive method for assessing bronchodilator responsiveness, although its application has received little attention among subjects with spinal cord injury. Use of body plethysmography might also confer greater discriminatory power for evaluating relationships between airway caliber and bronchodilator responsiveness. Last, the determination of sGaw would allow for direct comparisons with surrogate spirometric indexes of airway caliber in order to substantiate or refute previous findings. The primary aims of this study were therefore to determine baseline sGaw, to assess bronchodilator responsiveness by evaluating changes in sGaw following the inhalation of ipratropium bromide, and to correlate these findings with spirometric and plethysmographic lung volume parameters among subjects with tetraplegia and paraplegia, and able-bodied individuals.

MATERIALS AND METHODS

Thirty clinically stable male subjects, 15 with chronic cervical spinal cord injury (tetraplegia [injury at C4-C7]) and 15 with chronic thoracolumbar spinal cord injury (paraplegia [injury below T7]), participated in this study. Fifteen able-bodied individuals served as a control group. Subjects were selected who reported no history of pulmonary disease, atopy, or asthma, all of whom denied a history of recent or active pulmonary infections. None of the participants were receiving inhaled [[beta].sub.2]-adrenergic agonists or anticholinergic agents. The use of oral oxybutynin chloride and/or baclofen was permitted. Study participants with paraplegia and tetraplegia were recruited from among outpatients who were followed up at the spinal cord injury unit of the Bronx Veterans Affairs Medical Center. Control subjects were recruited from staff members on site. The study was approved by the institutional review board of the Bronx Veterans Affairs Medical Center, and informed consent was obtained prior to the investigation.

Lung volume and sGaw measurements were obtained during morning hours while subjects were seated in a variable-pressure, constant-volume, whole-body plethysmograph (model Vmax/ 6200 Body Plethysmograph; SensorMedics; Yorba Linda, CA). After allowing adequate time for thermal stabilization of the cabin, and with mouthpiece and nose clips attached, subjects began a period of baseline tidal breathing. Once stable tidal breathing was established, panting maneuvers were performed. Because subjects with tetraplegia were unable to manually support their cheeks, all study participants were instructed to minimize the use of their cheek muscles and to maintain an open airway while performing rapid and shallow panting maneuvers from functional residual capacity (FRC) at a frequency of approximately two cycles per second. These maneuvers were executed first with the automated breathing shutter open for the determination of airway resistance (Raw) and then closed for the determination of thoracic gas volume (Vtg), and were followed by a slow vital capacity maneuver for the measurement of inspiratory capacity and expiratory reserve volume (ERV). The Vtg and Raw were reported by calculating the ratio of closed and open shutter tangents, respectively, from graphs plotting simultaneous changes in mouth pressure (for Vtg determination) and flow (for Raw determination) against changes in body box pressure, averaged from three to five acceptable maneuvers. (11) Inspiratoly capacity was added to FRC to determine total lung capacity (TLC), and ERV was subtracted from FRC to obtain residual volume (RV). Raw was converted to conductance (Gaw) by taking its reciprocal, and Gaw was corrected for Vtg to determine sGaw.

Following the initial plethysmographic measurements, subjects remained seated in the body plethysmograph, and standard spirometry was performed according to American Thoracic Society standards. (12) As previously validated among subjects with tetraplegia, reproducible expiratory efforts were deemed acceptable in stone individuals despite back-extrapolated volumes that were in excess of the standard limits, and/or forced expiratory times of < 6 s in duration. (13) Lung volume and spirometric parameters were expressed as absolute values and the percent predicted was based on the prediction equations of Crapo et al (14) and the standards of Morris et al, (15) respectively.

On separate days, study participants underwent single-blind bronchodilator or placebo challenges. Baseline testing was completed first as described above, and then repeated 30 min after randomization and the administration of ipratropium bromide (2.5 mL 0.02% solution), or normal saline solution (2.5 mL 0.9% sodium chloride solution) via a nebulizer (model 8900; Salter Labs; Arvin, CA). Twelve participants who had been randomly selected from the groups with tetraplegia (6 participants) and paraplegia (6 participants) received ipratropium bromide, of whom 6 participants (3 from each group) received normal saline solution. The study was completed over approximately 1 year.

All data are expressed as the mean [+ or -] SD. A one-way analysis of variance was used to assess differences among subjects with tetraplegia, subjects with paraplegia, and able-bodied individuals. Post hoc analyses were conducted using Fisher pairwise comparisons, and, because of multiple comparisons, Bonferroni adjustments were applied. An unpaired Student t test was performed to compare baseline characteristics among the six subjects in each group with spinal cord injuries who received ipratropium bromide. A paired Student t test was used to assess the changes in pulmonary function parameters in response to ipratropium bromide and normal saline solution. Simple regression analysis was used to assess the relationships between baseline sGaw values and spirometric indexes of airway caliber (ie, FE[V.sub.1] and FE[F.sub.25-75%]) among all subjects (45 subjects), and between the relative percentage changes in sGaw and FE[V.sub.1] following the administration of ipratropium bromide (12 subjects). Statistical significance for these analyses was established at p < 0.05.

RESULTS

Background characteristics are shown in Table 1. Subjects with paraplegia and tetraplegia were similar in terms of age, body habitus, duration of injury, and smoking status. The control group included younger individuals, more never-smokers, and female subjects. The number of former smokers plus neversmokers compared to the number of current smokers, however, was similar in the three groups.

Baseline spirometric and plethysmographic parameters are presented in Table 2. Compared to control subjects, subjects with tetraplegia had lower absolute and percent predicted values for FVC, FE[V.sub.1], and FE[F.sub.25-75%], lower values for ERV and percent predicted TLC, and higher absolute values for RV and the RV/TLC ratio. Subjects with tetraplegia compared to subjects with paraplegia also had lower absolute and percent predicted values for FVC, FE[V.sub.1], and TLC, and lower percent predicted values for FE[F.sub.25-75%] and FRC. Compared to control subjects, subjects with paraplegia had higher values for Vtg, RV (absolute and percent predicted), and RV/TLC ratio, and lower values for ERV.

Measurements of sGaw are also shown in Table 2. The mean baseline sGaw was significantly reduced among subjects with tetraplegia (0.16 [+ or -] 0.05 cm [H.sub.2]O/s) compared to subjects with paraplegia (0.26 [+ or -] 0.05 cm [H.sub.2]O/s) or able-bodied individuals (0.27 [+ or -] 0.05 cm [H.sub.2]O/s). Specifically, 13 of 15 subjects with tetraplegia had sGaw values of < 0.20 cm [H.sub.2]O/s compared to none among subjects in the paraplegia or control groups.

Pulmonary function parameters before and after the administration of ipratropium bromide are shown in Table 3. No significant differences were found between the two groups of subjects with spinal cord injuries who received ipratropium bromide with regard to age, sex, height, weight, body mass index, or duration of injury (data not shown). Among subjects with tetraplegia, FVC, FE[V.sub.1], FE[F.sub.25-75%], ERV, and sGaw increased significantly (135%). Among subjects with paraplegia, the administration of ipratropium bromide was associated with significant, though comparatively smaller, increases in sGaw (19%). The inhalation of normal saline solution had no demonstrable effect on any spirometric or plethysmographic parameter (data not shown).

Linear regression analysis revealed a significant correlation among all subjects between baseline sGaw and surrogate spirometric indexes of airway caliber, including percentage of predicted values for FE[V.sub.1] (r = 0.71; p < 0.001) [Fig 1] and FE[F.sub.25-75%] (r = 0.63; p < 0.001) [data not shown]. Among subjects with paraplegia and tetraplegia, the percentage change in sGaw following the inhalation of ipratropium bromide correlated significantly with the percentage change in FE[V.sub.1] (r = 0.80; p < 0.002) [Fig 2].

DISCUSSION

We found that baseline sGaw was reduced in stable subjects with tetraplegia compared to subjects with paraplegia or able-bodied individuals. Traditionally thought to be an indirect measure of large airway caliber, (16) more recent reports have suggested that sGaw also reflects the diameter and patency of smaller airways, (17) an opinion supported by morphologic studies (18) in which the major resistance to airflow predominated in small-to-medium-sized airways. To the extent that sGaw is representative of the number, length, and patency of the conducting airways, (19) we therefore suspect that a reduction in baseline sGaw values among subjects with tetraplegia represents both large and small airway narrowing. This contention is supported by the significant correlation found among all study subjects between baseline measurements of sGaw and surrogate spirometric indexes of airway caliber (ie, FE[V.sub.1] and FE[F.sub.25-75%]). The presence of airway narrowing among subjects with tetraplegia also was suggested by other investigators using [sup.133]Xe scintigraphic techniques to assess regional ventilation, (20) and by the demonstration of the frequency dependence of lung compliance. (21)

The major determinant of Gaw is lung elastic recoil pressure (Pst[L]) to which Gaw varies directly. Consequently, an increase in Pst(L) at any given lung volume leads to a commensurate rise in Gaw, which is attributed to an increase in distending pressure exerted across airway walls. (19) Colebatch and colleagues, (22) by plotting total pulmonary conductance vs Pst(L) during interrupted expiration from TLC, discerned that the reduction in total pulmonary conductance among subjects with emphysema was due chiefly to a loss of elastic recoil, whereas a similar reduction in total pulmonary conductance among subjects with severe asthma was due primarily to intrinsic airway narrowing. (22) The majority of subjects with tetraplegia have decreased static pulmonary compliance, a finding theoretically linked to widespread microatelectasis, altered surfactant properties, and/or to decreased chest wall compliance. (23) Therefore, across any shared lung volume when compared to normal pressure-volume curves, Pst(L) is increased, and it follows that Gaw across these isovolumes should similarly be increased if the slope of the Gaw-Pst(L) relationship is preserved. Conversely, we found low baseline values for sGaw among subjects with tetraplegia, and, drawing on the findings reported by Colebatch et al (22) in asthmatic subjects, we have theorized that there is a decrease in the slope of the Gaw-Pst(L) relationship as a result of intrinsic airway narrowing. Of significance, sGaw measurements were included in several studies of subjects with chronic muscle weakness due to processes other than cervical cord injury. Although many subjects had reduced static lung compliance (24,25) comparable to that found among subjects with tetraplegia, (10,23) sGaw ranged from normal to high in three separate studies (24-26) that included 58 patients with miscellaneous myopathies. Therefore, our finding that subjects with tetraplegia have significantly reduced sGaw suggests a major difference in factors governing airway caliber among these individuals compared to those with general muscle weakhess.

The increases in sGaw (135%) and FE[V.sub.1] (260 mL; 12%) among subjects with tetraplegia who received ipratropium bromide meet the established criteria for significant bronchodilator responsiveness. (27,28) Among these subjects, findings of the normalization of sGaw, as evidenced by absolute increases in this parameter following the administration of ipratropium bromide, argue against the influence of technical errors leading to the low baseline sGaw values that we observed. Systematic error leading to the dependence of sGaw on Vtg, as has been described among healthy and asthmatic subjects, (29) also appears to be unlikely given the absence of significant changes in Vtg among subjects with tetraplegia before and after bronchodilator administration. Moreover, a spurious reduction in baseline sGaw and exaggerated bronchodilator responsiveness that might result from measurements of Vtg within the closing volume have not been substantiated by prior investigations involving subjects with tetraplegia that failed to demonstrate a closing volume by singlebreath washout curves, thereby suggesting airway patency at RV. (10,21) Findings that changes in sGaw correlated with changes in FE[V.sub.1] following ipratropium bromide administration, and that the inhalation of aerosolized normal saline solution had negligible effects, lend support to the use of body plethysmography for assessing bronchodilator responsiveness among subjects with spinal cord injury.

Because subjects with tetraplegia were unable to manually support their cheeks, a shunt capacitor effect during panting maneuvers may have led to changes in conductance and/or a minor overestimation of TLC, (30) possibilities controlled for by the adoption of the same panting technique among all study subjects. Inspiratory panting maneuvers performed primarily with the diaphragm, which is to be expected among subjects with spinal cord injury, might have resulted conversely in the underestimation of TLC. (31,32) Observations, however, among subjects with tetraplegia that lung volume measurements determined by whole-body plethysmography closely agree with those reported by prior investigators who used gas dilution techniques (10,21,23,33) lend credence to the applicability of this technique and to the interpretation of our results.

Many of the subjects with tetraplegia or paraplegia who are in the current study were receiving baclofen and/or oxybutynin chloride for the control of muscle spasms. Baclofen, a [lambda]-aminobutyric receptor agonist, presumably acts as a neuromodulator of the autonomic nervous system by inhibiting the release of both acetylcholine from cholinergic fibers and tachykinins from sensory C fibers. (34) Oxybutynin chloride acts as a potent antispasmodic agent, with moderate anticholinergic properties. (35) Studies of subjects with tetraplegia (36-38) have demonstrated that those subjects receiving baclofen or oxybutynin chloride had reduced responsiveness to methacholine, but not to histamine. It has not been determined whether baclofen or oxybutynin chloride affects baseline airway caliber in subjects with spinal cord injuries or whether responsiveness to ipratropium bromide is altered, but, based on the significant bronchodilator responses found among subjects with tetraplegia, it would seem that such effects, if any, are negligible.

One explanation for the significant increases in spirometric and plethysmographic parameters following the administration of ipratropium bromide in subjects with tetraplegia is heightened bronchomotor tone. Overriding cholinergic tone could result from the interruption of sympathetic innervation of the lungs, which originates in the upper six thoracic segments of the spinal cord, thereby leaving intact bronchoconstrictive parasympathetic activity carried by vagus nerves. Postganglionic sympathetic nerve fibers synapse in the middle and inferior cervical ganglia and in the upper four thoracic ganglia, and enter the hilum to intermingle with cholinergic nerves, where sympathetic fibers may modulate cholinergic neurotransmission. (39) Sympathetic fibers also innervate the smooth muscle layer of the human bronchial tree, with a few fibers reaching the level of secondary bronchi and terminal bronchioles. (40-43) In humans, however, the influence of sympathetic innervation on resting bronchomotor tone is unclear. (39) Another possible explanation for reduced sGaw in subjects with tetraplegia is the reduction in circulating epinephrine levels due to the interruption of the sympathetic innervation of the adrenal glands arising primarily from thoracic cord levels T10 to T12. (44) Epinephrine is derived entirely from the adrenal medulla and acts as a circulating hormone to participate in the regulation of bronchomotor tone through the stimulation of [[beta].sub.2] receptors. (39,45) Plasma levels of norepinephrine, a marker of overall sympathetic nerve activity, are also significantly reduced in subjects with tetraplegia. (44)

Other possible explanations for reduced airway caliber and airway hyperresponsiveness among subjects with tetraplegia include increased airway stiffness, retained secretions, and airway inflammation related to indolent infection. The extent to which inflammation induces structural changes within the airways and parenchyma in subjects with tetraplegia is unknown. Exaggerated airway narrowing also could be secondary to the inability of subjects to inhale deeply to the predicted TLC. (46) Findings, however, in the current study that airway caliber (sGaw) normalized following the inhalation of ipratropium bromide strongly suggests that pathologic changes and/or altered airway hysteresis were unlikely contributory factors.

ACKNOWLEDGMENT: The authors thank Dr. Peter Almenoff for his contribution to this work.

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* From the Spinal Cord Damage Research Center (Drs. Schilero, Bauman, Lenner and Lesser), The Bronx Veterans Affairs Medical Center, Bronx, NY; and the Basic Sciences Department (Dr. Grimm), New York Chiropractic College, Seneca Falls, NY. This research was supported by the Eastern Paralyzed Veterans Association.

Manuscript received February 3, 2004; revision accepted August 2, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Gregory J. Schilero MD, FCCP, The Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Rd, Bronx, NY 10468; e-mail: greg.schilero@med.va.gov

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