Gregory J. Schilero

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.

Relationship of respiratory symptoms with smoking status and pulmonary function in chronic spinal cord injury.

Abstract Objective: The relationship of respiratory symptoms to pulmonary function parameters and smoking status was assessed in subjects with chronic (>1 year) spinal cord injury (SCI). Methods and Participants: As part of their annual physical examination, subjects were queried regarding respiratory symptoms and underwent pulmonary function studies. The 180 patients who successfully completed pulmonary function testing were evaluated, including 79 subjects with tetraplegia (56 nonsmokers and 23 smokers) and 101subjects with paraplegia (78 nonsmokers and 23 smokers). Findings: Logistic-regression analysis revealed the following independent predictors of breathlessness: level of injury (tetraplegia, paraplegia, odds ratio = 3.5, P < 0.0015), cough combined with phlegm and/or wheeze (CPWZ, odds ratio = 3.1, P < 0.015), total lung capacity percentage predicted (TLC < 60%, odds ratio = 3.9, P < 0.02), and expiratory reserve volume (ERV < 0.6 L, odds ratio = 2.5, P < 0.05). Independent predictors of CPWZ were current smoking (odds ratio = 3.3, P < 0.004), breathlessness (odds ratio = 2.9, P < 0.03), and forced expiratory volume in 1second (FEV1 < 60%, odds ratio = 3.2, P < 0.01). Conclusion: Altered respiratory mechanics associated with tetraplegia contribute to breathlessness, restrictive ventilatory impairment (low TLC%), and reduced expiratory muscle strength (low ERV). These factors apparently overshadow adverse effects caused by smoking. Conversely, smoking and reduction of airflow (low FEV1%) were predictive of CPWZ, symptoms commonly associated with cigarette use.

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.

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.

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.

Salmeterol Improves Pulmonary Function in Persons with Tetraplegia

Abstractβ2-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 β2-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.

EFFECTS OF PEPTIDASE INHIBITORS ON BRADYKININ-INDUCED BRONCHOCONSTRICTION IN THE RAT

Objectives of this study were to determine if aerosolized bradykinin causes bronchoconstriction in anesthetized, mechanically ventilated rats, and if pretreatment with enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), or phosphoramidon, an inhibitor of endopeptidase 24.11 (EP 24.11), alters the response. We found that aerosolized bradykinin elicited a reproducible bronchoconstrictor response that was significantly amplified by pretreatment with aerosolized enalaprilat or phosphoramidon. Neither inhibitor alone affected airway tone or caused nonspecific airway hyperreactivity. These findings indicate that both ACE and EP 24.11 contribute to bradykinin degradation in rat airways.

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.

Greatly increased prevalence of esophageal dysmotility observed in persons with spinal cord injury

The effects of spinal cord injury (SCI) on esophageal motility are largely unknown. Furthermore, due to the complete or partial loss of sensory innervation to the upper gastrointestinal tract, a symptom-based diagnosis of esophageal dysmotility is problematic in the SCI population. To determine the prevalence and characterize the type of motility disorders observed in persons with chronic SCI compared with that of able-bodied (AB) controls based on esophageal pressure topography isometrics acquired by high-resolution manometry and categorized by application of the Chicago Classification. High-resolution manometry of the esophagus was performed in 39 individuals: 14 AB, 12 with paraplegia (level of injury between T4-T12) and 13 with tetraplegia (level of injury between C5-C7). A catheter containing multiple pressure sensors arranged at 360° was introduced into the esophagi of subjects at a distance that allowed visualization of both the upper esophageal sphincters (UES) and lower esophageal sphincters (LES). After a period to acquire pressures at baseline, subjects were asked to perform 10 wet swallows with 5-mL boluses of isotonic saline while esophageal pressure and impedance were being recorded. No significant differences were noted for gender, age, or body mass index between AB and SCI groups. Twenty-one of 25 (84%) subjects with SCI had at least one motility abnormality: 12% with Type II achalasia, 4% with Type III achalasia, 20% with esophagogastric junction outflow obstruction, 4% with the hypercontractile esophagus, and 48% with peristaltic abnormalities (weak peristalsis with small or large defects or frequent failed peristalsis). In contrast, only 7% (1 out of 14) of the AB subjects had any type of esophageal motility disorder. Despite the lack of subjective complaints and clinical awareness, esophageal dysmotility appears to be a highly prevalent condition in persons with SCI. The use of new and improved techniques, as well as a more stringent classification system, permitted the identification of the presence of nonspecific motility disorders in almost all SCI subjects, including four individuals who were previously undiagnosed with achalasia. Future work in persons with SCI is required to clarify the clinical impact of this observation and to study potential associations between esophageal dysmotility, gastroesophageal reflux disease, and pulmonary function. An increased awareness of esophageal dysfunction in the SCI population may lead to the development of new clinical guidelines for the diagnosis, prevention, and treatment of these largely unrecognized disorders.

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.