| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Department of Internal Medicine (Drs. Lechtzin and Wiener, and Mr. Shade), Division of Pulmonary and Critical Care Medicine, and the Department of Neurology (Ms. Clawson), Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: Noah Lechtzin, MD, MHS, 1830 E Monument St, Fifth Floor, Baltimore, MD 21205; e-mail: nlechtz{at}jhmi.edu
Abstract
Rationale: Lung compliance has been found to be low in patients with chronic diaphragmatic weakness or paralysis but has not been well-studied in patients with amyotrophic lateral sclerosis (ALS). Noninvasive positive-pressure ventilation (NPPV) prolongs survival in ALS patients but may also have additional beneficial effects.
Objectives: This study evaluated static expiratory lung compliance (CL) in subjects with ALS and determined the effect of lung inflation with supramaximal inflation on CL.
Design: This was a prospective trial comparing CL before and after supramaximal lung inflation via mouthpiece-delivered positive pressure.
Setting: A single university medical center with an multidisciplinary ALS center.
Participants: Fourteen subjects with ALS were compared to 4 healthy volunteers.
Interventions: Subjects underwent a battery of pulmonary function tests including for CL. Then they used positive pressure administered via a mouthpiece set to 10 cm H2O above their maximal static recoil pressure for 5 min. The CL measurement was then repeated.
Results: The mean (± SD) baseline CL was reduced (164.1 ± 82.1 mL/cm H2O) in subjects with ALS and was significantly lower than that in healthy volunteers (237.5 mL/cm H2O; p = 0.04). CL increased significantly in subjects with evidence of diaphragm weakness (change in CL, 11.3 ± 16.7 mL/cm H2O; p = 0.03). Healthy volunteers did not have an increase in CL.
Conclusions: Patients with ALS and diaphragmatic weakness have reduced CL, and brief supramaximal inflation increases CL. These findings suggest that atelectasis or increased alveolar surface forces are present in ALS patients and that these patients will have increased work of breathing. Some of the beneficial effects demonstrated with NPPV therapy may be through its effects on CL and the work of breathing.
Key Words: neuromuscular disease • noninvasive ventilation • pulmonary mechanics
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which most patients die from respiratory failure.12 Respiratory failure from neuromuscular disorders is thought to result from both progressive weakness of the inspiratory muscles as well as from the increased work of breathing from increased stiffness of the lungs and chest wall.3 Static lung compliance (CL) has been shown to be reduced in conditions causing respiratory muscle weakness, including muscular dystrophy, poliomyelitis, and cervical spine injury.4567 Muscular dystrophies generally are lifelong conditions in which respiratory muscle weakness develops very slowly. While changes in lung compliance in subjects with spinal cord injury appear to develop within a month of injury,4 much of our knowledge about the mechanics of quadriplegia comes from patients with more chronic weakness. Relatively little has been published on CL in patients with ALS, which is a relatively rapidly progressing, adult-onset disease. Patients with ALS often have demonstrable diaphragm weakness.8 The abnormally low CL in patients with neurologic disorders has been attributed to atelectasis,6 which may be subclinical, alterations in alveolar surface forces,9 or changes in the fibroelastic tissues of the lung.7
There are conflicting data on the effect of lung inflation using positive-pressure devices on CL. While one study10 showed marked increases in CL in subjects with kyphoscoliosis after treatment with intermittent positive-pressure ventilation, two subsequent studies1112 did not find any effect on CL in subjects with muscular dystrophies and spinal cord injury. This has not been evaluated in subjects with ALS.
Noninvasive positive-pressure ventilation (NPPV) is a frequently used intervention in subjects with ALS, and has been shown to prolong survival and improve quality of life.13141516 Some studies17 have also suggested that NPPV therapy can slow the decline in vital capacity that occurs in patients with ALS. It is not known whether NPPV simply provides ventilatory support for failed muscles or whether its benefits occur through additional mechanisms, such as decreasing the work of breathing by improving CL. This study tested the hypotheses that CL is reduced in subjects with ALS and diaphragmatic weakness, and that CL can be increased with short-term therapy with supramaximal lung inflation using positive pressure.
Materials and Methods
Subjects
Patients had probable or definite ALS by El Escorial criteria18 and had all been evaluated by a neurologist specializing in neuromuscular diseases. Control subjects were volunteers with no known pulmonary disease. Subjects were excluded if they were pregnant, had a neurologic disorder in addition to ALS, had kyphoscoliosis or other chest wall deformity, or had lung disease that was unrelated to ALS. Subjects signed written informed consent forms prior to study enrollment. This study was approved by the Johns Hopkins Institutional Review Board.
Pulmonary Function Testing
All tests were performed in the Johns Hopkins Hospital pulmonary function laboratory and met or exceeded applicable standards of the American Thoracic Society.19 All tests were performed with subjects in the upright seated position. Predicted values for vital capacity and total lung capacity (TLC) were based on the formulas of Goldman and Becklake.20
Maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) were measured with subjects in the seated position using a standard flanged mouthpiece. A 1 x 15-mm leak was present distal to the mouthpiece to prevent the participation of the orofacial muscles. PImax was measured from residual volume, and PEmax was measured from TLC. Transdiaphragmatic pressure (Pdi) was measured by maximal sniff from functional residual capacity (FRC) following the protocol of Miller et al.21 Two balloon catheters were inserted via the nares, were advanced fully, and were connected to differential pressure transducers. The esophageal balloon was gradually withdrawn from the stomach until the gastroesophageal junction was identified, and it was then withdrawn an additional 10 cm. Patients were instructed to make sharp, maximal sniffs from FRC. Pdi was derived electronically from the equation Pdi = gastric pressure – esophageal pressure and was continuously plotted on chart paper. Patients were instructed to watch the pen deflections caused by their efforts and to attempt to maximize the pen deflections. Sniffs were repeated until patients had at least three reproducible efforts. The highest Pdi achieved was recorded as the patient’s "Pdisniff." Arterial blood gas measurements were performed with a blood analyzer (ABL-520; Radiometer Medical; Brønshøj, Denmark). An arterial puncture of the radial artery or brachial artery was performed, and the sample was processed immediately.
CL was measured using the method of Gibson and Pride22 using the esophageal balloon that had been positioned for the measurement of Pdi. Transpulmonary pressure was recorded as the difference between the pressure at the airway opening (measured at the mouth) and that of the esophageal balloon. Subjects were asked to take two breaths to TLC followed by slow exhalation during which the mouthpiece was occluded at approximately 1-s intervals. Continuous measurements of lung volume and transpulmonary pressure were made during the exhalation maneuvers. Subjects performed at least three reproducible lung pressure-volume trials. Measurements of transpulmonary pressure and corresponding lung volume during periods of occlusion were recorded, and then were analyzed and plotted using specific software (SigmaPlot for Windows, version 7.0; SPSS; Chicago, IL). The transpulmonary pressure and lung volume values were recorded by individuals who were not investigators in the present study. Straight lines were fitted through the linear portion of the pressure-volume curves near FRC to provide the best estimated fit for each lung compliance trial performed. Static expiratory lung compliance is the slope of the fitted line and is reported in milliliters per centimeters of water. Pressures are expressed in milliliters per centimeters of water throughout, volumes are expressed in liters, and CL is expressed in milliliters per centimeters of water.
Experimental Protocol
Subjects underwent spirometry, lung volume measurement by helium dilution, PImax and PEmax measurement, and arterial blood gas measurement. Following these tests, esophageal and gastric balloons were inserted, and subjects had Pdi measured; at least three expiratory pressure-volume trials were performed. Subjects were then given positive-pressure ventilation through a mouthpiece while wearing nose clips. A bilevel positive-pressure ventilator (Quantum; Respironics; Murrysville, PA) was used for all subjects. The inspiratory pressure was set to the lower value of either 10 cm above the subjects’ previously measured maximum static recoil pressure or to 30 cm H2O. The inspiratory pressures delivered ranged from 19 to 30 cm H2O with a mean (± SD) of 22.8 ± 2.7 cm H2O in the subjects with ALS. The inspiratory pressures for the healthy volunteers ranged from 22 to 30 cm H2O with a mean of 26.8 ± 3.9 cm H2O. The expiratory pressure was set to 4 cm H2O. Subjects were asked to breath at a comfortable rate, and they were closely monitored for air leaks. Positive pressure was delivered for 5 min, and static expiratory lung compliance measurements were immediately repeated. Identical procedures were followed for ALS patients and healthy volunteers.
Statistical Analysis
Descriptive statistics are presented as the mean ± SD. Paired continuous variables were compared using the Wilcoxon signed rank test. Categoric variables were compared using the 
2 test. Associations between two continuous measures were assessed using simple linear regressions. Analyses were performed using a statistical software package (Stata Statistical Software, release 8.0; Stata Corporation; College Station, TX).
Results
Nineteen subjects with ALS were enrolled into the study. Five patients could not complete the study and were not included in the analyses. These patients were excluded for the following reasons: esophageal balloons could not be inserted in two subjects; two subjects could not perform the pressure-volume maneuvers due to bulbar muscle spasticity and lack of coordinated respiratory efforts; and one subject could not use the positive-pressure ventilator with a mouthpiece. Fourteen subjects with ALS and four healthy volunteers completed the protocol. Three subjects were not able to perform meaningful maximal inspiratory and expiratory measures, and four patients either refused arterial puncture or the technologists were unable to obtain a specimen.
The patients’ characteristics appear in Table 1 . They were similar to many ALS cohorts with a mean age of approximately 60 years, and 70% were male. Because patients with severe bulbar involvement had difficulty completing the protocol, the majority of patients had mild-to-no bulbar disease according to the ALS functional rating scale23 bulbar subscores of 10 to 12, with 12 indicating no speech, swallowing, or salivation symptoms. One subject had severe bulbar involvement with loss of speech and ability to swallow food. The healthy volunteers were pulmonary fellows in their late 20s to early 30s with normal lung function. None of the volunteers had previously undergone the measurement of lung compliance nor had they performed the lung inflation protocol.
|
|
|
|
|
|
|
This study demonstrated that, like other more long-standing causes of diaphragmatic weakness, patients with ALS have reduced CL. This reduction in lung compliance is related to the degree of impairment in vital capacity and lung volume, and not simply to the size of the subjects. Furthermore, we showed that lung inflation with high levels of positive pressure resulted in a significant improvement in lung compliance in subjects with diaphragm weakness and that the impact of positive pressure lung inflation was greater in subjects with more profound diaphragm weakness.
NPPV therapy is widely recommended for subjects with ALS and is usually initiated when a patient’s FVC falls to < 50% predicted.2425 The nocturnal use of NPPV in subjects with restrictive ventilatory defects has not only been shown to prolong survival,13141517 but has also been shown to improve daytime hypercapnia26 and fatigue.2728 There are also data suggesting that NPPV can slow the decline in FVC in subjects with ALS.1727 While NPPV may prolong survival by providing ventilatory support for subjects with respiratory failure, the mechanisms for some of the other beneficial effects are less clear. Our protocol did not mimic the typical use of NPPV. While there are no well-agreed on standards for ventilation therapy in patients with ALS, typical inspiratory pressures range from 8 to 22 cm H2O.272930 The average inspiratory pressure in this study was 23 cm H2O. Additionally, NPPV is generally used for at least 4 h per 24-h period by patients with ALS, and our study only evaluated subjects after 5 min of positive-pressure lung inflation. Nevertheless, our findings raise the possibility that NPPV therapy may exert beneficial effects by increasing CL. If NPPV use has this effect, it would result in decreased work of breathing for subjects with ALS. While the actual improvement in CL in this study was relatively small, subjects only used the positive-pressure ventilator for 5 min. It remains to be shown what effects the more prolonged use of positive-pressure ventilation with lower inspiratory pressures than those studied here have on CL. Additionally, the correlation between decreasing Pdi and increasing improvement in CL suggests that lung inflation may be increasingly beneficial as respiratory muscle weakness from ALS becomes more advanced.
Similar protocols have been performed previously in patients with other causes of restrictive ventilatory disorders and have yielded mixed results. Sinha and Bergofsky10 studied six patients with kyphoscoliosis and measured dynamic compliance before and after intermittent positive-pressure breathing (IPPB). Their protocol was similar to ours in many ways. They used IPPB for 5 min at an average pressure of 22 cm H2O. In their study, compliance increased from 79 to 115 mL/cm H2O. While this improvement is larger in magnitude than that in our study, positive-pressure ventilation could result in increases in airway caliber that may result in a greater change in dynamic compliance than in static compliance. Additionally, their subjects had greater impairment at baseline and therefore might be expected to benefit more from this intervention. A related study of IPPB has been done11 in muscular dystrophy patients and spinal cord-injured patients. IPPB was applied for 20 min at pressures from 20 to 25 cm H2O. In that study, respiratory system compliance was measured at baseline, then immediately after IPPB, and again at 30 and 90 min after IPPB. While the authors reported that compliance was not altered significantly 90 min after IPPB, the figures show relatively large increases in compliance in 11 of 14 subjects immediately after IPPB treatment. While the measurements of compliance are different from those of the current study and the patient population is quite different, the findings appear to be consistent with ours. Ferris and Pollard9 studied the effect of lung inflation on healthy subjects who had ventilation restricted with abdominal binders and on subjects with poliomyelitis. They were able to show increases in compliance with lung inflation either through the removal of the abdominal binders or through increasing negative pressures in tank ventilators to –30 to –35 cm H2O for 2 to 3 s. De Troyer and Deisser12 assessed changes in compliance before and after 15 min of IPPB in 10 subjects with muscular dystrophy. IPPB was set to 10 cm H2O above the static recoil pressure. The average pressure used was 29.1 cm H2O. The authors did not find an increase in CL. However, respiratory muscle weakness develops in patients with muscular dystrophy over a very long period of time and may not be comparable to ALS patients who experience a more acute disease process. De Troyer and Deisser12 hypothesized that low lung compliance in muscular dystrophy patients is the result of long-standing atelectasis that is not easily reversed by brief periods of lung inflation.
The mechanism for low lung compliance in subjects with neuromuscular disorders has been debated over the years. There are three proposed hypotheses, as follows: (1) atelectasis resulting in low compliance; (2) increases in alveolar surface forces; and (3) increased stiffness of lung elastic tissues from chronically limited movement. Any of these mechanisms could potentially be reversible by positive-pressure lung inflation but certainly the first two seem particularly amenable. Studies comparing lung compliance to specific lung compliance, or compliance divided by measured lung volume, have shown that specific lung compliance tends to be normal in patients with muscle weakness. The specific compliance should reflect the pressure-volume characteristics of the ventilated lung, suggesting that the low measured compliance reflects nonventilated or atelectatic areas.31 However, a study6 of chest CT scans in muscular dystrophy patients and patients with spinal cord injury revealed atelectasis in only 2 of 14 patients. The authors concluded that the reduction seen in compliance was not due to atelectasis and may have been due to a reduction in tissue elasticity.6 That belief was based in part on the conclusion that brief periods of lung inflation do not improve lung compliance, which the current study calls into question. Our protocol did not include radiologic studies of the patients, and unfortunately only 2 of the 14 subjects underwent chest radiography near the time of this study. Interestingly, these two patients both had atelectasis visible on their radiographs. The current study will not end the mechanistic debate, and it keeps alive the possibility that atelectasis and increased surface forces could contribute to the low CL in subjects with subacute onset of diaphragmatic weakness.
Interestingly, the healthy volunteers and the one patient with normal diaphragmatic strength had lower CL following lung inflation than before. While this was unexpected, it appears that these subjects achieved higher lung volumes when performing the expiratory pressure-volume maneuvers after lung inflation. This resulted in high lung volumes that were on the relatively flat portion of the pressure-volume curve.
We have demonstrated that patients with ALS have decreased CL. Most ALS patients die from pulmonary complications, and increased work of breathing due to low lung compliance may contribute to their pulmonary morbidity. Brief lung inflation with NPPV resulted in significantly higher lung compliance. This study provides further evidence that NPPV therapy can be beneficial in patients with ALS and should be considered as a therapeutic intervention, possibly even in patients with mild reductions in lung function or before FVC falls to < 50% predicted, as is often recommended. Aggressive lung volume recruitment maneuvers have been advocated for ALS patients. These results are consistent with that recommendation and support further study regarding the effect of lung inflation on pulmonary mechanics.
Footnotes
Abbreviations: ALS = amyotrophic lateral sclerosis; CL = static expiratory lung compliance; FRC = functional residual capacity; IPPB = intermittent positive-pressure breathing; NPPV = noninvasive positive-pressure ventilation; Pdi = transdiaphragmatic pressure; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; TLC = total lung capacity
This research was supported by National Heart, Lung, and Blood Institute grant K23 HL67887 and by the ALS Association. None of the authors have a financial interest with a commercial entity that has an interest in the subject matter discussed in this article.
Received for publication July 13, 2005. Accepted for publication October 22, 2005.
References
This article has been cited by other articles:
|
|
 |
|
  B. Fauroux, N. Guillemot, G. Aubertin, N. Nathan, A. Labit, A. Clement, and F. Lofaso Physiologic Benefits of Mechanical Insufflation-Exsufflation in Children With Neuromuscular Diseases Chest, January 1, 2008; 133(1): 161 - 168. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
