Traumatic Spinal Cord Injury: Pulmonary Physiologic Principles and Management.

In the United States, approximately 17,500 cases of traumatic spinal cord injury (SCI) occur each year, with an estimated 245,000 to 345,000 individuals living with chronic SCI. Acute management of respiratory dysfunction has resulted in improvement in early survival, but life expectancy remains less than that of the general population, and pulmonary complications are a leading cause of mortality. The global changes in pulmonary function, underlying pathophysiology, and the management options to improve respiratory muscle weakness and pulmonary clearance in persons with SCI are discussed. Given its high prevalence among subjects with cervical SCI, sleep disordered breathing is also discussed.

Bronchodilator effects of ipratropium bromide and albuterol sulfate among subjects with tetraplegia.

OBJECTIVE: In addition to lung volume restriction, persons with chronic tetraplegia demonstrate obstructive airway physiology evinced by pharmacologically-induced bronchodilation. We previously found independent evidence that anticholinergic agents (ipratropium bromide; IB) and beta-2 adrenergic agonists (albuterol sulfate; AS) were associated with significant bronchodilation in subjects with tetraplegia as determined via spirometry or body plethysmography. Direct comparison of these two classes of agents has received little attention. METHODS: Twelve subjects with chronic tetraplegia completed single dose treatment on alternate days with nebulized IB or AS. Patients underwent pre- and 30-minute post-bronchodilator spirometry, body plethysmography, and impulse oscillation system (IOS) in accordance with established protocols. RESULTS: Spirometry and specific airway conductance revealed significant bronchodilator responsiveness following both IB and AS. As determined by increases in specific airway conductance post-bronchodilator, IB tended toward greater bronchodilation than AS (71% vs. 47%). IOS revealed a greater reduction in central airway resistance (R20) following IB compared to AS (22% vs. 9%, P < 0.01). A greater number of subjects exhibited a clinically significant reduction in R20 following IB compared to AS (58% vs. 8%, P < 0.01). CONCLUSION: Among subjects with tetraplegia, both IB and AS elicit significant bronchodilation, although the magnitude of the bronchodilator response is greater following IB. This lends support to theory of overriding cholinergic airway tone in tetraplegia. The IOS findings further suggest that the predominant site of action of IB is upon the larger central airways congruent with findings in able-bodied subjects.

Biomarkers of inflammation in persons with chronic tetraplegia.

In addition to lung volume restriction, individuals with chronic tetraplegia exhibit reduced airway caliber and bronchodilator responsiveness similar to persons with asthma. In asthma, airflow obstruction is closely linked to airway inflammation. Conversely, little is known regarding the airway inflammatory response in tetraplegia. To compare levels of biomarkers of inflammation in exhaled breath condensate (EBC) and serum in subjects with chronic tetraplegia, mild asthma, and able-bodied controls.Prospective, observational pilot study. Thirty-four subjects participated: tetraplegia (n = 12), asthma (n = 12), controls (n = 10). Biomarkers in EBC [8-isoprostane (8-IP), leukotriene B4 (LT-B4), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6)] and serum (8-IP, LT-B4, TNF-α, IL-6) were determined using commercially available EIA kits (Cayman Chemical Company, Ann Arbor, MI). Separate, one-way ANOVA with Bonferroni's post-hoc analyses were performed to determine group differences in demographic and dependent variables [EBC and serum biomarkers, fractional exhaled nitric oxide (FeNO), pulmonary function parameters, and specific airway conductance (sGaw)]. The tetraplegia group had significantly elevated 8-IP levels in EBC compared to the asthma (68 ± 38 versus 21 ± 13 pg ml(-1); p < 0.001) and control groups (22 ± 13 pg ml(-1); p < 0.01), respectively. FeNO levels were significantly elevated in the asthma compared to the control group (26 ± 18 versus 11 ± 4 ppb; p < 0.05), and trended higher than levels in the tetraplegia group (15 ± 6; p = 0.08). Levels of serum biomarkers did not differ significantly among groups. Through analysis of EBC, levels of 8-IP were significantly elevated compared to levels found in individuals with mild asthma and healthy controls. Further studies are needed to extend upon these preliminary findings that suggest the presence of airway inflammation in subjects with chronic tetraplegia, and how this relates to pulmonary dysfunction in this population.

A center's experience: pulmonary function in spinal cord injury.

Traumatic spinal cord injury (SCI) is associated with significant psychological and physical challenges. A multidisciplinary approach to management is essential to ensure recovery during the acute phase, and comprehensive rehabilitative strategies are necessary to foster independence and quality of life throughout the chronic phase of injury. Complications that beset these individuals are often a unique consequence of SCI, and knowledge of the effects of SCI upon organ systems is essential for appropriate management. According to the National SCI Statistical Center (NSCISC), as of 2010 there were an estimated 265,000 persons living with SCI in the United States, with approximately 12,000 incidence cases annually. Although life expectancy for newly injured individuals with SCI is markedly reduced, persons with chronic SCI are expected to live about as long as individuals without SCI; however, longevity varies inversely with level of injury. Since 2005, 56 % of persons with SCI are tetraplegic, and due to paralysis of respiratory muscles, these individuals may be especially prone to pulmonary complications, which remain a major cause of mortality among persons with chronic SCI. We at the VA Rehabilitation Research and Development Center of Excellence for the Medical Consequences of SCI at the James J. Peters VA Medical Center have devoted more than 25 years to the study of secondary medical conditions that complicate SCI. Herein, we review pulmonary research at the Center, both our past and future endeavors, which form an integral part of our multidisciplinary approach toward achieving a greater understanding of and improving care for veterans with SCI.

31st g. Heiner sell lectureship: secondary medical consequences of spinal cord injury.

Persons with spinal cord injury (SCI) have secondary medical consequences of paralysis and/or the consequences of extreme inactivity. The metabolic changes that result from reduced activity include insulin resistance with carbohydrate disorders and dyslipidemia. A higher prevalence of coronary artery calcification was found in persons with SCI than that in matched able-bodied controls. A depression in anabolic hormones, circulating testosterone and growth hormone, has been described. Adverse soft tissue body composition changes of increased adiposity and reduced skeletal muscle are appreciated. Immobilization is the cause for sublesional disuse osteoporosis with an associated increased risk of fragility fracture. Bowel dysmotility affects all segments of the gastrointestinal tract, with an interest in better defining and addressing gastroesophageal reflux disease and difficulty with evacuation. Developing and testing more effective approaches to cleanse the bowel for elective colonoscopy are being evaluated. The extent of respiratory dysfunction depends on the level and completeness of SCI. Individuals with higher spinal lesions have both restrictive and obstructive airway disease. Pharmacological approaches and expiratory muscle training are being studied as interventions to improve pulmonary function and cough strength with the objective of reducing pulmonary complications. Persons with spinal lesions above the 6th thoracic level lack both cardiac and peripheral vascular mechanisms to maintain blood pressure, and they are frequently hypotensive, with even worse hypotension with upright posture. Persistent and/or orthostatic hypotension may predispose those with SCI to cognitive impairments. The safety and efficacy of anti-hypotensive agents to normalize blood pressure in persons with higher level cord lesions is being investigated.

Exhaled nitric oxide levels are elevated in persons with tetraplegia and comparable to that in mild asthmatics.

The role of airway inflammation in mediating airflow obstruction in persons with chronic traumatic tetraplegia is unknown. Measurement of the fraction of exhaled nitric oxide (FeNO) affords a validated noninvasive technique for gauging the airway inflammatory response in asthma, although it has never been assessed in persons with tetraplegia. This study was designed to determine the FeNO in individuals with chronic tetraplegia compared with that in patients with mild asthma and healthy able-bodied individuals. Nine subjects with chronic tetraplegia, seven subjects with mild asthma, and seven matched healthy able-bodied controls were included in this prospective, observational, pilot study. All subjects were nonsmokers and clinically stable at the time of study. Spirometry was performed on all participants at baseline. FENO was determined online by a commercially available closed circuit, chemiluminescence method, using a single-breath technique. Subjects with tetraplegia had significantly higher values of FeNO than controls (17.72 +/- 3.9 ppb vs. 10.37 +/- 4.9 ppb; P < or = 0.01), as did subjects with asthma (20.23 +/- 4.64 ppb vs. 10.37 +/- 4.9 ppb, P < or = 0.001). There was no significant difference in FeNO between subjects with tetraplegia and those with asthma (17.72 +/- 3.9 ppb vs. 20.23 +/- 4.64 ppb, P < or = 0.27). Individuals with chronic tetraplegia have FeNO levels that are comparable to that seen in mild asthmatics and higher than that in healthy able-bodied controls. The clinical relevance of this observation has yet to be determined.

Cold face test in persons with spinal cord injury: age versus inactivity.

INTRODUCTION: Persons with spinal cord injury (SCI) reflect a model of precocious aging and inactivity; as such, these individuals manifest well-appreciated cardiovascular abnormalities. We aimed to determine the influence of inactivity in persons with SCI, and the influence of age in healthy controls, on cardiovascular autonomic responses to the cold face test (CFT). METHODS: Subjects recruited (n = 42) included 18 controls: 10 young (25 +/- 2 years) and 8 old (50 +/- 6 years), and 24 subjects with chronic SCI: 17 with tetraplegia (C3-C8 44 +/- 7 years) and 7 with paraplegia (T5-T10 36 +/- 8 years). Heart rate (HR) and blood pressure were collected continuously: 2-min pre-CFT, 1-min CFT and 2-min post-CFT. Time-frequency (wavelet) analysis of HR (HFln) was used as an estimate of vagal cardiac modulation. RESULTS: The HR response to the CFT differed significantly among the SCI group (4.1 +/- 8.8 bpm) and the young (-7.7 +/- 5.9 bpm; P \ 0.001) and old (-6.8 +/- 10.7 bpm; P \ 0.01). The HFln response was reduced in the SCI (0.01 +/- 1.59) as compared with the young controls (1.50 +/- 1.50; P \ 0.05), but was not different from the old controls (0.69 +/- 1.39). The bradycardia did not differ among the young and old controls; however, the vagal response was attenuated in the old compared with the young. These data suggest that age does not significantly alter the heart rate response to the CFT, but attenuates the vagal response. CONCLUSION: In the SCI group, the paradoxical heart rate response to facial cooling and the lack of vagal activation suggest that abnormal autonomic cardiovascular reflexive control may result from profound inactivity and/or from the spinal cord injury per se.

Pulmonary function and spinal cord injury.

Injury to the cervical and upper thoracic spinal cord disrupts function of inspiratory and expiratory muscles, as reflected by reduction in spirometric and lung volume parameters and static mouth pressures. In association, subjects with tetraplegia have decreased chest wall and lung compliance, increased abdominal wall compliance, and rib cage stiffness with paradoxical chest wall movements, all of which contribute to an increase in the work of breathing. Expiratory muscle function is more compromised than inspiratory muscle function among subjects with tetraplegia and high paraplegia, which can result in ineffective cough and propensity to mucus retention and atelectasis. Subjects with tetraplegia also demonstrate heightened vagal activity with reduction in baseline airway caliber, findings attributed to loss of sympathetic innervation to the lungs. Significant increase in airway caliber following inhalation of ipratropium bromide, an anticholinergic agent, suggests that reduction in airway caliber is not due to acquired airway fibrosis stemming from repeated infections or to abnormal hysteresis secondary to chronic inability of subjects to inhale to predicted total lung capacity. Reduced baseline airway caliber possibly explains why subjects with tetraplegia exhibit airway hyperresponsiveness to methacholine and ultrasonically nebulized distilled water. While it has been well demonstrated that bilateral phrenic nerve pacing or stimulation through intramuscular diaphragmatic electrodes improves inspiratory muscle function, it remains unclear if inspiratory muscle training improves pulmonary function. Recent findings suggest that expiratory muscle training, electrical stimulation of expiratory muscles and administration of a long-acting beta(2)-agonist (salmeterol) improve physiological parameters and cough. It is unknown if baseline bronchoconstriction in tetraplegia contributes to respiratory symptoms, of if the chronic administration of a bronchodilator reduces the work of breathing and/or improves respiratory symptoms. Less is known regarding the benefits of treatment of obstructive sleep apnea, despite evidence indicating that the prevalence of this condition in persons with tetraplegia is far greater than that encountered in able-bodied individuals.

Airflow obstruction and reversibility in spinal cord injury: evidence for functional sympathetic innervation.

OBJECTIVES: The first objective was to assess group differences for specific airway conductance (sGaw) among subjects with tetraplegia, high paraplegia (HP: T2-T6), and low paraplegia (LP: T10-L4). The second objective was to determine the significance of responsiveness to ipratropium bromide (IB) by the assessment of the inherent variability of baseline measurements for impulse oscillation (IOS), body plethysmography, and spirometry. DESIGN: Prospective cross-sectional intervention study. SETTING: James J. Peters Veterans Administration Medical Center. PARTICIPANTS: Subjects (N=43): 12 with tetraplegia (C4-8), 11 with HP, 11 with LP, and 9 controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measurement of IOS, body plethysmography, and spirometry parameters at baseline and 30 minutes after IB. RESULTS: Baseline sGaw was significantly lower in tetraplegia (0.14+/-0.03) compared with HP (0.19+/-0.05) and LP (0.19+/-0.04) patients. By use of minimal difference to evaluate IB responsiveness in tetraplegia, 4 of 12 and 12 of 12 subjects had significant increases in forced expiratory volume in 1 second and sGaw, respectively, whereas 11 of 12 and 10 of 12 subjects had significant decreases in respiratory resistances measured at 5 and 20 Hz (R5 and R20), respectively. CONCLUSIONS: The finding of group differences for baseline sGaw supports the hypothesis that human lung contains functional sympathetic innervation. Body plethysmography and IOS were comparable in detecting IB-induced bronchodilation in tetraplegia and significantly more sensitive than spirometry.

Salmeterol improves pulmonary function in persons with tetraplegia.

beta(2)-Adrenergic agonists are known to improve muscle strength because of anabolic properties. The purpose of this study was to determine if long-term administration of a long-acting beta(2)-adrenergic agonist to subjects with tetraplegia is associated with improvement in pulmonary function parameters and maximal static inspiratory and expiratory mouth pressures (MIP and MEP, respectively), measures of respiratory muscle strength. The study was a randomized, prospective, double-blind, placebo-controlled, crossover trial and conducted at the James J. Peters Veterans Affairs Medical Center. Thirteen subjects who had complete or incomplete tetraplegia for more than one year participated in the study. Eleven subjects completed the study. All were clinically stable outpatients without any history of asthma or use of inhaled bronchodilators. Following baseline measurements, patients were randomized to receive salmeterol or placebo from identically marked Diskus containers for 4 weeks. Following a 4-week washout period, the subjects were randomized to receive the alternate preparation for 4 weeks. Pulmonary function parameters and static mouth pressure were measured during baseline and during the fourth week of the two study periods. During the 4-week period of salmeterol administration, forced vital capacity, forced expiratory volume in 1 s, peak expiratory flow, MIP, and MEP improved significantly compared with placebo and baseline. Expiratory reserve volume increased significantly compared to baseline. Increases in MIP and MEP during salmeterol administration suggest improvement in respiratory muscle strength. However, this cannot be stated with certainty because MIP and MEP are dependent on volume parameters at which they are measured. Regardless of the mechanism, improvement in static mouth pressures indicates that salmeterol should benefit these individuals by improving cough effectiveness.

Assessment of airway caliber and bronchodilator responsiveness in subjects with spinal cord injury.

STUDY OBJECTIVES: Previous spirometric findings among subjects with chronic tetraplegia that reduction in FEV1 and maximal forced expiratory flow, mid-expiratory phase (FEF(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 effort-dependent 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, including 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 H2O/s), total lung capacity, FVC, FEV1, and FEF(25-75%) compared to subjects in the other two groups. Subjects with tetraplegia who received ipratropium bromide experienced significant increases in sGaw (135%), FEV1 (12%; 260 mL), and FEF(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.

Effects of neostigmine and glycopyrrolate on pulmonary resistance in spinal cord injury.

Preliminary findings in subjects with spinal cord injury (SCI) suggest that neostigmine administered intravenously increases colonic tone, increases colonic contractions, and facilitates bowel evacuation. Of concern are potential pulmonary side effects, including an increase in airway secretions and bronchospasm. The objectives of the study were to determine the effects of intravenously administered neostigmine or neostigmine combined with glycopyrrolate on forced oscillation indices in persons with SCI. Pulmonary resistances at 5 Hz (R5) and 20 Hz (R20) were measured with the use of an impulse oscillation system (IOS) in 11 subjects with SCI. Values were obtained before and after the intravenous administration of 2 mg of neostigmine alone and, on a separate day, before and after the administration of 2 mg of neostigmine combined with 0.4 mg of glycopyrrolate. Baseline R5 and R20 values before neostigmine correlated significantly with baseline values before neostigmine combined with glycopyrrolate. Following neostigmine, mean R5 values increased 25% and mean R20 values increased 18%. Following neostigmine combined with glycopyrrolate, mean R5 values fell 9% and mean R20 values fell 7%. In summary, baseline IOS values obtained on 2 different days were highly reproducible in this population. Neostigmine alone induced significant bronchoconstriction, whereas neostigmine combined with glycopyrrolate caused bronchodilation.

Bronchodilator responses to metaproterenol sulfate among subjects with spinal cord injury.

A previous study using spirometric methods demonstrated that 42% of subjects with tetraplegia experienced significant bronchodilation following inhalation of metaproterenol sulfate (MS). Comparative studies involving subjects with paraplegia were not performed and none has been performed in this population using body plethysmography, a more sensitive method used to assess airway responsiveness. Stable subjects with tetraplegia (n = 5) or paraplegia (n = 5) underwent spirometry and determination of specific airway conductance (sGaw) by body plethysmography at baseline and 30 minutes after nebulization of MS (0.3 mL of a 5% solution). Among subjects with tetraplegia, inhaled MS resulted in significant increases in spirometric indices and sGaw. Among subjects with paraplegia, only sGaw increased significantly, although this increase was considerably less than that seen in subjects with tetraplegia. Our findings indicate that subjects with tetraplegia exhibit greater bronchodilation in response to inhaled MS than do subjects with paraplegia and that sGaw measurements may confer greater sensitivity for assessing bronchodilator responsiveness in tetraplegia.

Comparison of lung volume measurements in individuals with spinal cord injury by two different methods.

BACKGROUND/OBJECTIVE: Few detailed studies have been performed among subjects with spinal cord injury (SCI) using whole body plethysmography for measurement of static lung volumes. Because abdominal gas volumes and respiratory patterns among subjects with varying levels of SCI may differ significantly from able-bodied individuals, methodological concerns related to this technique could conceivably lead to inaccuracies in lung volume measurements. The purpose of this study was to compare lung volume parameters obtained by whole body plethysmography with those determined by the commonly used nitrogen washout technique among individuals with SCI. PARTICIPANTS: Twenty-nine clinically stable men, 14 with chronic tetraplegia (injury C4-C7) and 15 with paraplegia (injury below T5) participated in the study. METHODS: Lung volumes were obtained using whole body plethysmography and the open-circuit nitrogen washout technique. Within both study groups, data were evaluated by the paired Student's t test and by determination of correlation coefficients. RESULTS: No statistically significant differences for any lung volume parameter were found within either group. In subjects with tetraplegia on paraplegia, respectively, strong correlation coefficients were found for measurements of total lung capacity (.86 and .97), functional residual capacity (.87 and .96), and residual volume (.77 and .85). CONCLUSION: These findings indicate that body plethysmography is a valid technique for determining lung volumes among subjects with SCI. Because airway resistance measurements can also be obtained during same study sessions for assessment of airway caliber and bronchial responsiveness, body plethysmography is a useful tool for examining multiple aspects of pulmonary physiology in this population.

Sarcoidosis presenting in patients older than 50 years.

BACKGROUND: Sarcoidosis occurs most often between 20 and 40 years of age, but also presents in children and older adults. Newly diagnosed sarcoidosis in older patients has received little attention. In order to characterize sarcoidosis in older patients, the clinical, radiographic and laboratory features of sarcoidosis presenting in patients aged 50 or older were compared to patients whose sarcoidosis was diagnosed at an earlier age. METHODS: The medical records of 181 consecutive patients with sarcoidosis were reviewed. They were divided into 92 patients diagnosed at 50 years of age or older (group A), and 89 whose diagnosis preceded age 50 (group B). RESULTS: Comparison of group A with group B revealed that the two groups were similar with regard to race, gender, smoking habits, common presenting symptoms, organ system involvement, pulmonary function data, radiographic stage, PPD status, and laboratory values. At the time of diagnosis, most patients in both groups presented with either respiratory symptoms or asymptomatic chest roentgenogram abnormalities. The most prevalent pulmonary function abnormality was reduced diffusing capacity in both groups. Most patients exhibited either stage I or II chest roentgenograms. Organ systems most commonly involved included lung, lymph nodes, and skin. CONCLUSION: Sarcoidosis presents with similar clinical features whether diagnosed in young adults or in patients over the age of 50. The diagnosis of sarcoidosis should be considered in patients presenting over age 50 with characteristic signs and symptoms including chest radiographic evidence of mediastinal lymphadenopathy.

Donor-acquired sarcoidosis.

"Donor-acquired sarcoidosis" is defined as the development of sarcoidosis in presumably naïve (non-sarcoidosis) transplant recipients who have received tissues or organs from donors who were not known or suspected to have active sarcoidosis. In reviewing the literature up until September of 1999, we found four publications describing a total of eight organs or tissues donated by subjects with sarcoidosis. These are the basis for this review. We draw upon these cases to discuss etiologic considerations for sarcoidosis, and suggest that donor-acquired sarcoidosis strengthens the view that sarcoidosis is caused by a transmissible agent, perhaps of infectious origin. Since not all recipients of organs from donors with active sarcoidosis develop sarcoidosis, host factors also appear to be important in disease pathogenesis. Less credence is ultimately given to external or environmental factors. Issues underlying host tolerance as a possible explanation for the reported absence of mortality or loss of allograft function during the limited periods of observation are also discussed.

Hemoptysis: diagnosis and management.

Hemoptysis is a frightening and potentially life-threatening symptom. However, most cases can be approached effectively with conservative management. Bronchial artery embolization should be attempted when bleeding is refractory to medical therapy, and surgery may be needed in severe hemorrhage.