Respiratory Complications in Neuromuscular Disorders

Daniel M. Goodenberger, MD

Respiratory Complications in Neuromuscular Disorders

Respiratory management of patients with neuromuscular diseases has been highly successful in reducing morbidity and extending survival. The monitoring and therapy described subsequently will be based on the available literature. In areas in which a scientific basis for management is insufficient, conflicting, or nonexistent, recommendations will be based on the author's more than 21 years of experience in the area and his position as the only pulmonary consultant in this field at a major medical center. In the penultimate 6 years at this center, the author was involved in the ongoing care of 170 patients with amyotrophic lateral sclerosis (ALS) and 134 other patients with neuromuscular disease, principally muscular dystrophies. Thus, many recommendations are derived from that experience; in instances in which the recommendations are different from those of other authors, the reasoning will be outlined.

Management of Neuromuscular Diseases Resulting in Chronic Respiratory Failure The evaluation of patients with neuromuscular diseases that result in chronic respiratory failure does not usually involve a primary diagnosis. Most patients presenting to a pulmonologist with these disorders already have a diagnosis that has been made or verified by a referring neurologist. Detailed descriptions of the initial presentation and evaluation of these diseases are provided elsewhere in this book and will not be repeated here except to make illustrative points about therapy that may differ by disease process. Bilateral Diaphragm Paralysis Exceptions are patients who present with dyspnea as a result of diaphragmatic weakness or paralysis and do not yet have a diagnosis or etiology. This condition may be caused by muscle weakness as a result of metabolic (hypothyroidism1), inflammatory (systemic lupus erythematosus; vanishing lung syndrome2), or myopathic (Pompe disease3,4) causes. It may also be caused by phrenic nerve injury as a result of cardiac surgery5 (a common current cause), trauma, inflammation (neuralgic amyotrophy6), hereditary neuropathy (Charcot-Marie-Tooth or Dejerine-Sottas, spinal muscular atrophy), or motor neuron disease presenting first in this way.7

2

Patients with unilateral diaphragm paralysis are rarely symptomatic unless there is underlying lung disease. Symptoms that should lead the clinician to suspect bilateral diaphragm paralysis include profound orthopnea, with which the patient is unable to lie completely flat for more than a few seconds. The patient may have mild to moderate dyspnea at rest that is severely exacerbated by bending sharply at the waist, as when tying the shoes. The patient will invariably describe an inability to submerge in water above the waist, which results in profound dyspnea. This results from interference with a primary compensatory mechanism. These individuals have learned to function by using their abdominal expiratory muscles to force the diaphragm upward to a level below functional residual capacity; during inspiration, the muscles are relaxed and the abdominal viscera pull the diaphragm down by gravity, augmenting inspiration. The buoyant effect of the water prevents this, resulting in a feeling that patients call “suffocating.” Physical examination shows the use of accessory muscles in the neck, and the patient generally ensures that the upper extremities are supported to provide mechanical advantage. Expiratory use of abdominal muscles may be detected. In the supine position, the patient invariably has paradoxical motion, with the abdomen moving in rather than out with inspiration. Careful percussion of the chest may show failure of normal diaphragmatic excursion. The general history and physical examination should focus on possible underlying disease processes that may produce diaphragm paralysis. Neuralgic amyotrophy is a brachial plexitis that results in severe shoulder pain preceding the onset of dyspnea. Patients with adult Pompe disease may have associated proximal muscle weakness. Primary respiratory-onset ALS may be associated with pathologic reflexes and fasciculations. Primary underlying diseases, such as lupus, hypothyroidism, and previous trauma, including surgery, should be sought. The first test conducted to confirm the diagnosis is the “sniff” test, during which the patient forcefully sniffs through the nose while chest fluoroscopy is performed. This test is excellent for confirming the diagnosis of unilateral paralysis; the unaffected diaphragm descends rapidly and normally, and the affected diaphragm rises while the mediastinal structures move toward the unaffected side. However, if performed while the patient is upright, it may miss bilateral paralysis; as described earlier, passive fall of the diaphragm during inspiration may confound the examiner and result in a report

21

22 General Principles in the Treatment and Management of Neuromuscular Disorders

of normal diaphragmatic function.8 To be effective, fluoroscopy must be performed with the patient supine; in this position, paradoxical diaphragmatic excursion will be seen. Ultrasound may also be used to assess diaphragmatic movement.9 Confirmatory tests include pulmonary function tests, measurement of diaphragmatic pressure generation, and electrodiagnostic studies. Spirometry generally shows a reduction in forced vital capacity (FVC) of approximately 50%. Lung volumes are restrictive, with a pattern that the majority of reduced lung volumes are in the voluntary portion of spirometry. Residual volume is generally preserved. Characteristically, FVC is reduced by an additional 40% or more in the supine position. Maximum inspiratory pressure, achieved by asking the patient to inhale with greatest force from residual volume against a manometer, is typically reduced from normal and can be measured in the pulmonary function laboratory. Occasionally, an otherwise healthy patient can generate surprisingly high pressures, approaching normal. Maximum expiratory pressure (measured from total lung capacity) is generally preserved. Maximum transdiaphragmatic pressure, or PDImax (the difference between esophageal pressure and gastric pressure, which requires balloon manometry in both organs), is always reduced, usually less than 30 cm H2O. Reproducibility is improved by using a sniff technique.10 This technique is beyond the capacity of most clinical pulmonary function test laboratories and is seldom necessary. Similarly, nerve conduction studies of the phrenic nerves and diaphragmatic electromyograms may be performed, but are seldom necessary for clinical diagnosis. When they are believed to be required, they are best performed in a laboratory with substantial experience with the techniques. Because of their profound orthopnea, these patients are generally sleeping in a chair at presentation. Therapy is indicated at the time of diagnosis. Most patients can be treated successfully with nocturnal noninvasive ventilation,11 which is initiated as described later. Diaphragmatic pacing is not indicated in these patients; this procedure requires both intact phrenic nerves and normal muscle function, and it is generally limited to patients with high spinal cord injuries and intact phrenic nerves and patients with central alveolar hypoventilation.12 Assessment and Management of the Patient with an Established Neurologic Diagnosis Most patients seen by a pulmonologist as outpatients fall into one of two groups: those with muscular dystrophy and those with motor neuron disease. The approach to these patients is discussed separately because their monitoring and care are different. Depending on local referral patterns, ventilator-dependent patients with spinal cord injury and those with post-polio syndrome requiring ventilatory support may also be seen and will be discussed briefly. Other diseases that may have respiratory involvement include inflammatory myopathies, critical illness polyneuropathy, myasthenia gravis, Eaton-Lambert syndrome, intoxications, Guillain-Barré syndrome, botulism, and porphyria. However, these diseases do not generally result in chronic respiratory failure and will be discussed in the section of the chapter on management of acute respiratory failure. Muscular Dystrophies The most common of the hereditary neuromuscular disorders requiring chronic mechanical ventilation is Duchenne muscular dystrophy. The young men with this disease have a relatively similar course, being wheelchair-bound by roughly 12 years of age and having respiratory

failure by the late teens or occasionally as late as the early 20s. Occasionally, the first manifestation is acute respiratory failure after a lower respiratory tract infection or surgical procedure. More often, the onset is insidious. The patients do not often have dyspnea as the primary symptom; presumably this is because by this point they are invariably bed- and wheelchair-bound, the latter being driven by electric motors. Occasionally, the presentation is weight loss, which seems to be caused by postprandial dyspnea, or occasionally by early satiety because of very slow eating. Often, patients have evidence of sleep disturbance or nocturnal hypoventilation, with daytime sleepiness, morning headaches, and nightmares that may involve smothering. The headaches are characteristic, being present on awakening and clearing within 1 hour or less without intervention, and are caused by nocturnal hypercapnea. Sleep abnormalities are common in Duchenne muscular dystrophy before the onset of frank respiratory failure, and a polysomnogram may be necessary to identify the nocturnal disturbances.13 This appears to have become more common after the widespread prescription of corticosteroids, which may result in substantial weight gain. It is not uncommon to have hypoventilation with hypercapnea and secondary hypoxemia, particularly during rapid eye movement sleep. Occasionally, nocturnal hypoventilation is sufficiently severe by the time of evaluation to result in right heart failure out of proportion to left ventricular function; this is less common now because most such individuals are followed by neuromuscular specialists who are alert to respiratory dysfunction and refer patients earlier than in the past. The second most common muscular dystrophy requiring ventilatory support is myotonic dystrophy. There is not a characteristic age of onset because the severity of the symptoms is influenced by the length of the responsible CTG trinucleotide repeats. Because of trinucleotide expansion from generation to generation (“anticipation”), a physician caring for several generations of the same family can expect onset of respiratory failure a decade or more earlier in each successive generation. Sleep apnea is common in myotonic dystrophy, and a substantial minority of patients has excessive daytime sleepiness, even without respiratory failure. As a consequence, polysomnography should be performed in sleepy patients, even if they have normal gas exchange. Earlier studies attributing hypoventilation to abnormal respiratory drive were based on ventilatory response to carbon dioxide; the interpretation of the results was confounded by muscle weakness reducing minute ventilation, the measured variable. Later studies using inspiratory pressure during the first 100 msec of inspiration (P0.1) suggest normal ventilatory response.14 Myotonia of the diaphragm is undoubtedly present, but of uncertain significance in the development of respiratory symptoms. A less common X-linked muscular dystrophy also caused by a dystrophin mutation is Becker muscular dystrophy. These patients follow a course very similar to that of Duchenne muscular dystrophy, but with each milestone, including the development of respiratory failure, delayed in onset by approximately a decade. Other hereditary muscular dystrophies (limb-girdle, facioscapulohumeral, Emery-Dreifuss) are less likely to result in respiratory failure, but may do so on occasion. All symptomatic patients should be evaluated. At a minimum, pulmonary function tests, including FVC, lung volumes, maximum inspiratory and expiratory pressures, oximetry, and arterial blood gases on room air, should be performed. A baseline chest x-ray will be helpful in evaluating subsequent respiratory infections, particularly if there are baseline abnormalities in heart size, spinal structure or hardware, pulmonary parenchyma, or diaphragm placement.

Respiratory Complications in Neuromuscular Disorders 23

Symptoms of sleep apnea should prompt a sleep study. Symptomatic dysphagia or recurrent pneumonias suggesting aspiration (uncommon in muscular dystrophy in my experience) may be evaluated by modified barium swallow or fiberoptic evaluation of swallowing by a speech pathologist.15 All patients should have appropriate influenza and pneumococcal vaccinations. If the individual has significant dysphagia or evidence of aspiration, or more commonly, weight loss associated with dyspnea, gastric tube placement should be considered. Although there is no direct evidence that improved nutrition results in better respiratory outcome, it seems reasonable to prevent muscle loss attributable to malnutrition. Moreover, weight loss may lead to loss of soft tissue on the buttocks and back, making both bed and wheelchair use very uncomfortable. As described later, we prefer gastric tube insertion by interventional radiology, not least because it allows respiratory support more readily than percutaneous endoscopic gastric tube placement. Monitoring of patients who are asymptomatic is arbitrary, particularly given the evidence that prophylactic or early initiation of ventilatory support is not helpful and appears to be harmful, at least in Duchenne muscular dystrophy.16 When FVC is 50% or less than predicted, it is reasonable to follow handheld spirometry in the neuromuscular clinic and refer patients for formal evaluation to obtain the formal pulmonary function testing described earlier. If the patient is asymptomatic, repeat visits and evaluations are scheduled at 6- to 12-month intervals, depending on status and gestalt. Because of the possibility of life-threatening complications of even apparently minor respiratory infections (discussed later), patients and their caregivers are told to seek care promptly at onset. Pulmonary function tests in these muscular dystrophies characteristically show restriction, with normal flow rates (normal ratio of forced expiratory volume in 1 second to FVC and normal midexpiratory flow). In contrast to the restriction seen in pulmonary fibrosis, however, the majority of volume reduction occurs in the voluntary, spirometric components that depend on muscle strength. Thus, FVC and its subdivisions are much more reduced than functional residual capacity or residual volume, whereas in fibrosis, all components are reduced more or less proportionately (Fig. 2-1). Most of the reduction is probably the result of muscle weakness, although there is some evidence that chronic breathing at low lung volumes reduces pulmonary compliance. Some of this is likely caused by microatelectasis and surfactant loss, but some appears to be the result of poorly understood reductions in chest wall compliance.17,18 As a result, functional residual capacity (determined by the relative Restrictive Patterns

RV Normal

FRC

Paralysis

Kyphoscoliosis

Pulmonary fibrosis

Figure 2-1 Patterns of restriction. FRC, functional residual capacity; RV, residual volume.

elasticity of the lungs and chest wall) may be mildly reduced. Residual volume may appear increased because weak expiratory muscles may reduce the expiratory reserve volume, used to calculate residual volume after functional residual capacity is determined. Maximum inspiratory and expiratory pressures have the advantage that they are easily measured with a handheld manometer and nose clips. The disadvantage is that there is a wide range of normal values, as determined by multiple studies, affected by age, sex, ability to form and maintain a tight mouth seal, and general health. Normal maximum expiratory pressure, measured from residual volume after a full exhalation, is roughly
120 cm H2O for men and approximately
90 cm H2O for women, with a broad range. Corresponding values for maximal expiratory pressure, measured from total lung capacity after a full inhalation, are approximately þ230 cm H2O for men and þ150 cm H2O for women. Values of less than 30 cm for maximum inspiratory pressure are often accompanied by hypercapneic respiratory failure. Because this test adds little or nothing to spirometry and arterial blood gases, which are repeated at every routine visit, I do not routinely follow these tests. Respiratory management of patients with muscular dystrophy is the subject of strongly held opinion but a relative paucity of evidence based on controlled clinical trials. Inspiratory muscle training has been suggested to build respiratory muscle strength and improve respiratory status. There is little evidence to support this, however. Moreover, initiation of noninvasive ventilation in hypercarbic patients invariably results in reduction in daytime PCO2, suggesting that these damaged muscles are fatigued and benefit from rest. As a result, resistive training is not part of our regimen. Similarly, we do not use theophylline as a respiratory muscle “tonic.” Because expiratory muscles are weak, some practitioners routinely use a mechanical in-exsufflator to improve sputum removal.19,20 These devices, based on the original Coughalator (J.H. Emerson Co., Cambridge, MA; now Philips Respironics, Murrysville, PA), rapidly inflate and then deflate the lungs, generating high airway velocities. Pressures are gradually increased as tolerated to achieve maximum pressures of approximately 40 cm H2O for both the inspiratory and expiratory components. Controlled data supporting the use of this device in patients with stable muscular dystrophy are lacking. In our experience, these patients have normal (but often small) airways and do not clinically have excess mucus production in the uninfected state. As a consequence, use of this device has not been a routine part of management for our patients. Cough assistance can, however, provide substantial benefit for these patients when they have a lower respiratory infection (discussed later). Evidence of respiratory failure or serious nocturnal hypoventilation is generally considered an indication for initiation of ventilatory support.21 These factors include daytime hypercapnea and nocturnal hypoventilation (demonstrated by sleep study or recording nocturnal oximetry, particularly when accompanied by the symptoms described earlier). Although there is virtually no evidence of benefit rising to the level of controlled clinical trials, the longitudinal experience of multiple groups is unequivocal in showing that noninvasive positive pressure ventilation (NPPV) improves symptoms, quality of life, and longevity,22,23 compared with studies that showed very poor survival in the absence of ventilatory support once vital capacity is less than 1 L or once nocturnal hypoxemia and daytime hypercapnea occur.24,25 Although individual groups have been using mouthpiece NPPV for many years,26,27 the most common devices used for noninvasive ventilation until the mid-1980s were negative pressure ventilators.28

24 General Principles in the Treatment and Management of Neuromuscular Disorders

Figure 2-4 Cuirass ventilator with user. Figure 2-2 Iron lung.

The Drinker respirator (iron lung) was in wide use in the United States and abroad during the polio epidemics in the mid-20th century. The patient lies on a padded platform that slides into the cylinder, with an airtight seal achieved via a gasket around the neck (Fig. 2-2). Intracylinder negative pressure was generated by a piston, which in turn resulted in thoracic expansion and inspiration. Respiratory rate and tidal volume were regulated by piston stroke frequency and stroke length, respectively. In those with normal thoracic cages, adequate tidal volumes were generated by pressures of
12 to
25 cm H2O. For those with significant deformity, as in the case of severe kyphoscoliosis, higher negative pressures were required. Tidal volumes may be measured with a Wright spirometer. These ventilators continued to be used by polio patients requiring respiratory assistance and were adapted for use by patients with chest wall deformities and neuromuscular disease. However, they were cumbersome and difficult to enter for patients with neuromuscular disorders, caused soreness around the neck, made routine hygiene needs difficult, and worsened sleep apnea in patients with neuromuscular failure.29,30 Fiberglass cuirass ventilators worked on the same principle, but were less effective, had a limited number of sizes, and could not be used on those with thoracic deformities (Figs. 2-3 and 2-4). Poncho (raincoat) ventilators used a frame that could accommodate variations in body habitus and was covered by fabric with seals at the neck, wrists, and pelvis (Fig. 2-5). However, it could be used only in the supine position, leading to discomfort, and it was drafty because of

Figure 2-3 Cuirass ventilator (“turtle shell”).

air leaks. Because of inefficiencies in thoracic expansion, each of these required greater negative pressures, typically
20 to
40 cm H2O. Other respiratory assist devices included the rocking table and pneumobelt. The rocking table rotated from the head up to the head down position and back at a variable rate. This allowed the abdominal viscera to participate in diaphragmatic movement and assist respiration (Fig. 2-6). The pneumobelt functions in much the same way that the abdominal expiratory muscles do in diaphragmatic paralysis, inflating during expiration to force the diaphragm and abdominal viscera cephalad, with passive fall on inhalation (Figs. 2-7 and 2-8). The patient must be sitting or standing for this to be effective. Pressures required are generally 30 to 50 cm H2O.31 These devices are largely of historical interest, and descriptions of these kinds of treatments can be expected to disappear over the next decade. They are included in this discussion because occasional patients may be seen who continue to use these in various combinations (iron lung or rocking bed at night, pneumobelt in the daytime). Most of these patients have used these devices since their bout of acute poliomyelitis or required resumption of ventilatory support as a result of post-polio syndrome. Alba and colleagues32 have used NPPV by mouthpiece for decades. This ventilatory modality was revolutionized by the introduction of positive pressure by nasal mask in the mid-1980s.33,34

Figure 2-5 Poncho ventilator.

Respiratory Complications in Neuromuscular Disorders 25

Figure 2-6 Rocking bed. Figure 2-9 Facial mold for custom mask.

Figure 2-7 Pneumobelt.

Figure 2-8 Pneumobelt in use.

The vast majority of NPPV is now delivered by nasal interface, although some patients require or benefit from oronasal masks or mouthpieces. Initiation of nasal positive pressure ventilation is best done in the hospital; mask fit, ventilator education, selection of ventilator settings, family education, and troubleshooting can often be accomplished in a 36- to 48-hour admission encompassing 2 nights. Mask selection is a matter of individual choice and comfort. The original masks, designed for continuous positive airway pressure, were more likely to cause erosions and breakdown at the nasal bridge and maxillary spine. Early on, this led some of us to seek out prosthodontists to make custom masks based on facial impressions (Fig. 2-9). However, newer-generation masks with softer silicone (Silastic; Dow Corning, Midland, MI) seals and gel cushioning have reduced the discomfort (Fig. 2-10). Nevertheless, some patients tolerate intranasal interfaces (pillows) better (Fig. 2-11), and interchange of the two kinds of devices may allow continuous use until the nasal skin or mucosa becomes more resistant to injury.35–37 Continuous positive airway pressure and bilevel positive airway pressure masks are designed with holes for air leak. Combined with

Figure 2-10 Softfit Ultra mask (Puritan Bennett, Boulder, CO).

26 General Principles in the Treatment and Management of Neuromuscular Disorders

Figure 2-11 ADAM circuit (nasal pillows) (Puritan Bennett, Boulder, CO).

expiratory positive pressure, the holes minimize CO2 rebreathing. If volume ventilation is used, these masks must be modified or they cannot be used. If assist-control ventilation is used with a nasal mask leak, the patient may find it impossible to trigger the ventilator, or rapid autocycling may occur. Home respiratory therapists, accustomed to bilevel positive airway pressure, are unfamiliar with this and may be resistant to change; they must be instructed carefully. In the beginning, most ventilation was performed with volumecontrolled portable home ventilators. Bilevel positive airway pressure devices, originally designed for more comfortable treatment of sleep apnea, have evolved into more sophisticated ventilators and have largely supplanted volume ventilators for noninvasive treatment, both in the United States and in Europe.38,39 This likely has its genesis in the near-simultaneous development of pressure support ventilation, the familiarity of large numbers of pulmonologists with these devices compared with the much smaller numbers familiar with portable volume ventilators, and aggressive marketing of these machines by manufacturers and durable medical equipment companies; they are substantially less expensive and are amortized more quickly. In one instance, a durable medical equipment company refused to provide a volume ventilator for a patient without a tracheostomy, citing nonexistent Medicare regulations. Interactions with the company suggested that this refusal sprang from financial motives. There is no evidence of difference in outcomes supporting the choice of one mode over the other,40–42 although there is some suggestion that patients find pressure mode more comfortable. Models include BiPAP ST-D and related devices (Respironics), GoodKnight 425ST (Nellcor Puritan Bennett, Boulder, CO), and VPAP ST (Resmed, Poway, CA). If pressure mode is chosen, pressures necessary to provide adequate tidal volume and rest the respiratory muscles must be chosen. There is good evidence that inspiratory pressure of approximately 15 cm H2O is necessary to silence the diaphragmatic electromyogram.43 (Some authors have suggested that it may be necessary to start at lower pressures and increase them gradually; that has not been my experience when ventilation is initiated in the hospital and pressures are based on tidal volume and minute ventilation.) The most frequent reason for unsatisfactory results from pressure ventilation in my experience is inadequate inspiratory pressures; it is not uncommon to find patients referred for a second opinion with settings of inspiratory positive airway pressure/expiratory positive airway pressure of 8/4 to 10/5. On the occasions when I use bilevel positive pressure ventilation, inspiratory pressure is set to achieve a

tidal volume of approximately 10 mL/kg, and the backup rate is set to achieve a minute ventilation of approximately 100 mL/kg. Expiratory pressure is not used as external positive end-expiratory pressure, but is used solely for the purpose of purging carbon dioxide from the mask; 4 to 5 cm H2O is generally adequate. I use volume ventilation nearly exclusively in patients with muscular dystrophy. First, episodes of acute respiratory failure superimposed on the chronic state are most often precipitated by infection. Typically, these infections are viral and accompanied by nasal congestion. As a result, when patients need additional ventilatory support, they get less; the increased nasal resistance reproducibly results in lower tidal volumes and minute ventilation. Moreover, increased lower airway secretions result in substantial variations in airway resistance and relatively wide swings in minute ventilation over short periods. Second, many of these patients transition to tracheostomy ventilation over a decade or so. When they do, they and their families are already fully familiar with the ventilator they will use. Originally, I followed a fairly intensive protocol for initiation, adjusting respiratory rate and tidal volume based on arterial blood gases.44 Over time, it became apparent that this was ineffective and unnecessary. Currently, tidal volumes and respiratory rates are initially chosen based on the patient's size and weight, to achieve tidal volumes and minute ventilation in the range described earlier. These are adjusted by well-trained respiratory therapists overnight based on comfort and compliance. Results are reviewed the next morning, and further adjustments are made under direct observation during the day. The second night is usually more successful than the first, and after teaching and troubleshooting, the patient is discharged. The ventilator mode is usually assist-control, although intermittent mandatory ventilation with pressure support is a comfortable alternative. Oxygen administration during this process is less likely to cause problems in this group of patients than in those with ALS, but should be avoided (discussed later). Common problems during initiation and thereafter include mask air leak, which may result in eye irritation and exposure keratitis; skin breakdown; nasal congestion and dryness; and stomach bloating. The mask leak can usually be corrected with strap adjustment and appropriate support of ventilator tubing (Fig. 2-12). This

Figure 2-12 Ventilator tubing support.

Respiratory Complications in Neuromuscular Disorders 27

in turn will reduce eye irritation; early on, it may be necessary to provide eye lubricant. Skin irritation and breakdown can be helped with padding, application of moleskin, and alternating between mask and nasal pillows. Gastric distention may be treated with simethicone, but it usually abates on its own over the first 2 weeks. In-hospital initiation allows observation for oral leaks. If they occur, they may be corrected with a chinstrap. If initiation occurs on an outpatient basis and results are suboptimal, nocturnal family observation or recording oximetry may show ineffective ventilation. Home care arrangements are crucial. If possible, the home respiratory team should meet with the patient and physician in the hospital so that expectations and instructions are fully understood by both parties. Family instruction is equally important. The patient is seen and evaluated after 3 to 4 weeks. With few exceptions, daytime PCO2 will have diminished to less than 50 mm Hg, regardless of the starting point. The mechanisms remain uncertain; reduction of chronic muscle fatigue likely plays a part, but a significant role may be played by “resetting” central chemoreceptors to new, lower levels of nighttime PCO2.45 Thereafter, the patient is seen regularly at intervals of 3 to 6 months. Early on, increases in daytime PCO2 are often caused by reductions in nocturnal use and will respond to increases. Over several years, it will be necessary to increase duration of ventilation to achieve the same results. This may be conveniently applied during an afternoon nap. Over the ensuing years, the required duration increases, and often over a decade or so, continuous ventilation becomes necessary. Many patients can be ventilated comfortably and successfully with nasal ventilation, but as the ability to tolerate ventilator-free time decreases, ventilator failure or mask displacement becomes increasingly hazardous. Nevertheless, some choose to continue NPPV indefinitely. Previous generations of portable ventilators (LP-10, Nellcor Puritan Bennett; PLV-100, Respironics) required modifications of wheelchairs to accommodate daytime use, with a platform on the back that increased turning radius and could interfere with van transport. More modern ventilators, such as the LTV-900 or -1000 (Pulmonetics, now Cardinal Health, Dublin, OH) and Puritan Bennett 540 (Nellcor Puritan Bennett), are small enough to be suspended from the back of the wheelchair in a hanging bag, which is much more convenient (Figs. 2-13 and 2-14). Some experts believe that noninvasive ventilation is preferable to tracheostomy ventilation at all costs, using daytime mouthpiece ventilation mounted via gooseneck on the wheelchair and nighttime mask or oronasal interface.46 I am not of that persuasion. At the

Figure 2-13 LTV-900 ventilator (Pulmonetics; now Cardinal Health, Dublin, OH).

Figure 2-14 LTV-900 ventilator (Pulmonetics, now Cardinal Health, Dublin, OH) on wheelchair.

point at which the patient requires continuous ventilation, I prefer tracheostomy. In the event of ventilator failure, ventilation may be continued much more safely and conveniently with an Ambu bag. At least some of the reluctance to this approach is an incorrect belief that tracheostomy is incompatible with speech and normal oral intake. When a mutual decision is reached to undertake tracheostomy, elective admission is arranged. In the postoperative period, a cuffed tracheostomy tube is used; the air leak associated with an uncuffed tube may result in subcutaneous emphysema, pneumomediastinum, and pneumothorax. This is continued for 7 to 10 days, until the tissue planes are sealed. During this time, communication may be maintained with an electrolarynx. After healing, the cuffed tube is exchanged for an uncuffed tube. This should be sized to allow adequate exhalation with the tube plugged; this may require endoscopic evaluation. Fenestrated tubes should be avoided: no matter how carefully they are sized, the fenestration will rub on the anterior tracheal wall at the stoma and result in the formation of granulation tissue; unfenestrated tubes virtually never do so. Although it is possible for a patient to produce speech while ventilated with an uncuffed tube alone, the speech pattern is noncontinuous and occurs during inspiration, a nonintuitive process. The use of a one-way valve in-line with the ventilator (Passy-Muir speaking valve; Passy-Muir Inc., Irvine, CA) allows normal speech (Figs. 2-15 and 2-16). As a beneficial side effect, speech is often stronger because greater tidal volumes are delivered. Aspiration is uncommon; severe dysphagia is unusual in the muscular dystrophies, and most patients can continue oral intake after becoming accustomed to the tracheostomy and having a confirmatory swallowing evaluation. Moreover, the positive pressure exhalation helps to clear perilaryngeal secretions. The instructions for the Passy-Muir valve call for removal at night.

28 General Principles in the Treatment and Management of Neuromuscular Disorders

Valve placement for use with ventilatordependent patients

Passy-Muir tracheostomy speaking valve connects directly to tracheostomy tube with 15-mm hub

Wide-mouth short flex tubing slides over valve

B

A

Adapter connects short flex tubing to respiratory line

Figure 2-15 Passy-Muir speaking valve (Passy-Muir Inc., Irvine, CA).

in patients with Duchenne muscular dystrophy in particular has greatly increased cardiomyopathy-induced dysrhythmias as a cause of death, leading to increased use of beta-adrenergic blockers and, on occasion, automated implantable cardiac defibrillators. Nutrition is not usually an issue. Those who have been able to eat preoperatively are generally able to continue after a suitable interval and appropriate swallowing evaluation. Those who have been fed by gastric tube because of dyspnea and weight loss may be able to resume oral feedings; given the normal expiratory flow allowed by a one-way valve, aspiration risk is reduced. Spinal Cord Injury

Figure 2-16 Telemarketing with Passy-Muir speaking valve (Passy-Muir Inc., Irvine, CA).

I know of no practical reason for this, and routinely continue to ventilate the patient at night with a cuffless tube and speaking valve. This greatly improves nocturnal communication with caregivers. Tracheostomy impairs the ability to cough, and suctioning is necessary. Family members must be taught the proper technique. Long experience shows that clean technique is adequate; inner cannulae may be cleaned with soap, water, and hydrogen peroxide and reused. There is no need for routine tracheostomy changes; they may be changed for wear and tear, signs of irritation, or infection. Inhaled adrenergic bronchodilator drugs are virtually never needed and should be avoided in those patients with underlying cardiomyopathy. The prolonged survival

Spinal cord injury above C4 often is associated with paralyzed diaphragms as well as paralysis of the scalene, intercostal, and abdominal muscles; sternocleidomastoid innervation remains intact. As a result, 40% of those with C3 injury remain ventilator-dependent, as do all or nearly all of those with higher lesions. Very high lesions may leave the phrenics intact but nonfunctional, with the potential for electrical stimulation later. Lesions below C5 leave the neck accessories and diaphragms intact, but lower intercostals and abdominals are nonfunctional. All patients eventually become ventilator-independent, but because of impaired cough and secretion clearance, they may have problems with major atelectasis, most often in the left lower lobe. This may result in short-term respiratory failure. For patients with permanent ventilator dependence, tracheostomy ventilation with ventilator speech, as described earlier, represents the best choice, but not all experts agree.47 For patients with very high lesions and demonstrable phrenic function by nerve conduction studies and diaphragmatic electromyogram, electrophrenic respiration may be an option.

Respiratory Complications in Neuromuscular Disorders 29

Persistent Polio Disability and Post-Polio Syndrome

A relatively small number of patients who had polio in the 1950s with an ongoing need for ventilatory support remain. They may continue to use the noninvasive modalities described earlier, including rocking beds, pneumobelts, and negative pressure ventilators. Others have converted to NPPV or may have an interest in doing so. An increasing number of patients with recurrent symptoms resembling their original poliomyelitis began to be seen in the 1980s. The latent period appeared to be 20 to 30 years. Gradually progressive weakness was seen in the distribution of the original symptoms; patients requiring ventilatory assistance were generally those who had required mechanical ventilation during the original illness. These patients can be managed in a way similar to those with muscular dystrophy. Because the polio epidemics ended with the widespread administration of the Salk polio vaccine more than 50 years ago, it can be assumed that few additional cases will be seen. Motor Neuron Diseases Spinal Muscular Atrophy

The most common form of spinal muscular atrophy, and the most common type to cause respiratory dysfunction and the need for ventilatory support, is type II, with onset in early childhood and slowly progressive motor dysfunction. The age at which ventilatory support is needed varies, but it is often in the 20s. It is not uncommon for respiratory function to plateau for variable periods. Without intervention, scoliosis is common and adds to the respiratory dysfunction. Ventilatory management is similar to that for the muscular dystrophies. Amyotrophic Lateral Sclerosis

ALS, a disease of both upper and lower motor neurons, differs from the muscular dystrophies in several important aspects that affect respiratory management. The course of the disease is much more rapid: average time from onset to death is approximately 3 years. Although approximately 80% of patients have onset in an extremity and 20% have initial bulbar involvement, all eventually have bulbar incompetence, leading to dysphagia, trouble handling oral secretions, and aspiration, if they live long enough. Finally, in contrast to the muscular dystrophies, all patients eventually lose the power of speech, in addition to having quadriplegia, and ultimately have great difficulty communicating by any mode. The treating neurologist should follow the vital capacity and refer patients for pulmonary evaluation when it approaches 50% predicted. Performance of the vital capacity is dependent on adequate seal around the mouthpiece and so is susceptible to inaccuracy with bulbar involvement. In that case, sniff nasal inspiratory force may be used to follow the patient.48 A value of less than 40 cm H2O is associated with nocturnal hypoxemia and a median 6-month survival rate of 50%. Blood gases should also be obtained when it is not possible to follow vital capacity, when there is dyspnea or orthopnea, or when there is hypoxemia on pulse oximetry. The American Academy of Neurology consensus guidelines recommend consideration of noninvasive ventilation when one of the following is present: FVC less than 50%, orthopnea, stiff nasal pressure less than
40 cm, or MIP less than
60 cm.49 This recommendation is based on a single randomized controlled trial comparing noninvasive ventilation to standard care in a total of 41 patients with orthopnea and NIP less than 60% predicted or symptomatic daytime hypercapnia.50 The study design and results do not permit extrapolation to asymptomatic individuals or to those earlier in the disease course. Survival and quality of life were improved in patients without severe bulbar dysfunction. Other

nonrandomized studies have shown improved survival and quality of life in those without bulbar involvement who could tolerate NPPV.51,52 My own practice is to outline ventilatory support options at the patient's first visit, regardless of the stage of respiratory involvement. The guidelines for patient information outlined by the American Academy of Neurology are followed, and ample time is allowed for questions. The subject is addressed at each subsequent visit. The option of withdrawal of support under patient control and with comfort measures is made explicit; that is, patients clearly understand that, having decided on tracheostomy ventilation, their rescinding that decision will not be met by opposition or legal action on the part of the treating physician.53–56 Using this approach, and with information presented uniformly by a single physician expert, my experience with the most recent 170 patients has been that fewer than 6% opt for tracheostomy ventilation and fewer than 30% wish noninvasive ventilation. The rest of the patients opt for supportive care. Quality of life appears to be improved for patients who are offered NPPV after respiratory symptoms develop.57 The quality of life of caregivers for patients using NPPV does not appear to be negatively affected, in contrast to tracheostomy ventilation.58,59 Patients undergoing tracheostomy ventilation may be satisfied with that mode, although experience is more mixed.60 Those choosing NPPV undergo initiation in the hospital in much the same way as those with muscular dystrophy. As with patients with muscular dystrophy, these patients have modest or no alveolar–arterial gradient. Hypoxemia is generally caused by hypercapnea. Before the initiation of ventilatory support, many of these patients have substantial nocturnal hypercapnea and hypoxemia. In the early stages of noninvasive ventilation, this will persist. The night nursing staff must understand that they must not give patients oxygen without direct physician involvement because it may result in severe hypercapnea, even on mask ventilation.61 Despite these precautions, unordered nocturnal oxygen administration has resulted in hypercapneic coma detected on morning bedside rounds; nursing notes recorded that the patient “slept comfortably.” These patients can usually be revived without endotracheal intubation, using full-face mask ventilation under the supervision of the attending physician at the bedside for 1 hour or more. Attempts at NPPV in patients with bulbar involvement, even with full-face masks, are nearly uniformly unsuccessful. Those without bulbar involvement can often be supported successfully as long as that condition obtains, sometimes for up to several years. These are the exceptions, and the usual course is more rapid deterioration. Dysphagia and aspiration predispose patients to respiratory infections that may result in acute respiratory failure. Patients should understand that this is likely to be the case. Tracheostomy ventilation is initiated, for those desiring it, in a way similar to that described for muscular dystrophy. Because most have bulbar dysfunction, risk of aspiration, and loss of speech, ventilation with a cuffed tracheostomy tube is usually appropriate. The cuff should be inflated using minimal leak technique, and cuff pressure should be measured. Ideally, cuff pressure should be 15 to 20 mm Hg and always less than 25 mm Hg. Monitoring by caregivers at home may help to reduce the incidence of tracheomalacia and tracheoesophageal fistula, which is already very low, in my experience, in these patients whose ventilator pressures are usually low. Tracheostomy tubes may be changed on an as-needed basis, when the balloon fails. It is not necessary to change the tube on a scheduled basis because balloon failure does not generally result in significant difficulty ventilating patients with normal compliance for short periods. Ideally, the caregiver should be taught to change the tube, but it may also be

30 General Principles in the Treatment and Management of Neuromuscular Disorders

changed in the clinic or emergency room. A spare inner cannula should be kept on hand and cleaned as described earlier. Recent reports have suggested that diaphragmatic pacing may be useful in patients with ALS.62,63 Evidence of efficacy is offered by comparing rates of decline in FVC before and after laparoscopic placement of electrodes after mapping. Given the highly variable rates of respiratory decline over time in the same patient, it seems prudent to await the results of controlled, appropriately randomized clinical trials before adopting this as standard therapy. Adjuncts that may increase comfort and forestall complications are available. Control of sialorrhea may reduce microaspiration. A variety of anticholinergic agents may be used (I prefer glycopyrrolate and hyoscyamine liquids because they are easily titratable. Having an oropharynx that is too dry is nearly as bad as one that is too wet). Salivary injection of botulinum toxin has been used by some, although concerns remain that this may result in worsening of the underlying disease; parotid radiation may be used as a last resort. Portable suction is also useful. Gastric tube placement allows nutrition without aspiration on swallowing (although reflux aspiration may still occur). Percutaneous endoscopic gastrostomy tube placement should be done while FVC is more than 50%. I prefer to have the tube placed with interventional radiology because it avoids esophageal intubation, reduces the need for sedation, and allows noninvasive respiratory support during the procedure. For those desiring only symptomatic care, comfort is usually achievable. Home nursing services or home hospice care can assist the patient's family.64 Oxygen may be given without regard to Medicare guidelines. Opioids are generally effective in relieving dyspnea and may be administered by a variety of routes. Transdermal fentanyl beginning at 25 µg every 72 hours may be titrated upward as needed. Liquid morphine may be administered orally or via gastric tube. Morphine may also be effective for dyspnea when administered via nebulizer. Benzodiazepines are effective at relieving anxiety.

Management of Neuromuscular Diseases Resulting in Acute Respiratory Failure Acute respiratory failure in patients with neuromuscular disease generally falls into one of two categories. First are the patients with an acute illness, such as Guillain-Barré syndrome, which results in respiratory failure as part of its natural history, and which, with appropriate care, is reversible, with return to normal respiratory function. Second are patients with chronic neuromuscular disease with respiratory involvement who have a crisis requiring initiation or extension of ventilatory support, such as ALS or one of the muscular dystrophies discussed earlier. Guillain-Barre´ Syndrome Guillain-Barré syndrome is the most common neuropathy precipitating respiratory failure. The typical case is marked by paresthesias, ascending paralysis, and loss of deep tendon reflexes. Between 15% and 30% of patients ultimately require mechanical ventilation. Poor prognostic factors include rapid progression, bulbar dysfunction, bilateral facial weakness, and autonomic dysfunction.65,66 Patients with these characteristics should be admitted to an intensive care unit, with frequent neurologic and respiratory monitoring. Vital capacity should be measured with a bedside spirometer, and maximum inspiratory pressures should be monitored.67 Factors associated with the development of respiratory failure and portending the need for mechanical ventilation include vital

capacity of less than 20 mL/kg, maximal inspiratory pressure of less than 30 cm H2O, maximal expiratory pressure of less than 40 cm H2O, or a reduction of more than 30% in vital capacity, maximal inspiratory pressure, and maximal expiratory pressure.68 Other factors that predict the need for mechanical ventilation include severely impaired cough and inability to clear secretions and weakness so profound that the patient cannot raise the arms or head.69 Oximetry and blood gases should be monitored. When the course strongly predicts the need for mechanical ventilation, endotracheal intubation should be performed before the patient is in crisis. The procedure can be done electively and in a controlled fashion. Orotracheal intubation is preferred to nasotracheal intubation because it allows a larger tube size and avoidance of nosocomial sinusitis. NPPV is not often successful because the need for ventilation is frequently for 2 weeks or longer and because of bulbar dysfunction, secretions, and autonomic instability. Care from that point is supportive. The duration of need for mechanical ventilation may be shortened by plasmapheresis or intravenous immunoglobulin. Liberation from mechanical ventilation is the norm, although prolonged ventilation may be required. Standard weaning parameters are followed by T-tube or pressure support ventilation trials, depending on the preference of the critical care team. If mechanical ventilation exceeds 10 to 14 days, particularly if there is little progress, tracheostomy will improve the patient's comfort and nursing care. Myasthenia Gravis Myasthenia gravis does not ordinarily require long-term respiratory support. However, abrupt deterioration (myasthenic crisis) may precipitate respiratory failure. This may be caused by infection, a surgical procedure (a number of anesthetic agents and neuromuscular blockers may exacerbate myasthenia gravis), or reduction of immunosuppressive therapy. It may also occur after administration of any of a large number of drugs that may interfere with neuromuscular transmission. The best known are the aminoglycoside antibiotics; however, a large number of other antibiotics, beta-adrenergic blockers, anticonvulsants, and antipsychotics may also cause deterioration. The medication list of the deteriorating patient should be reviewed carefully and compared with one of the widely available contraindicated drug lists. In earlier times, cholinergic crisis as a result of anticholinesterase therapy was a serious part of the differential diagnosis. The increasing role of immunosuppression and avoidance of high-dose anticholinesterase administration has made this much less common. As a result, edrophonium administration (Tensilon test) for differentiation is no longer used routinely. Patients with progressive and significant weakness should be admitted to an intensive care unit. Vital capacity and maximum inspiratory pressure (also known as negative inspiratory force) should be measured frequently.70 The goal is to avoid uncontrolled emergency intubation as well as to anticipate the need in a way that allows a controlled, elective procedure. Orotracheal intubation should be considered if the vital capacity falls to 15 to 20 mL/kg, maximum inspiratory pressure is less than 25 to 30 cm H2O, the patient has bulbar dysfunction interfering with secretion and airway control, or the patient is in significant respiratory distress. Oximetry and blood gases should be monitored.71 In general, noninvasive ventilation is not appropriate because of bulbar involvement. Once mechanical ventilation is required, anticholinesterase medication is discontinued and therapy with either plasmapheresis or intravenous immunoglobulin is begun, depending on local capabilities and preference. After this therapy, anticholinesterase

Respiratory Complications in Neuromuscular Disorders 31

medication may be resumed and high-dose steroids may be initiated or resumed. Liberation from mechanical ventilation follows standard ventilatory parameters and weaning protocols. Miscellaneous Conditions A wide variety of medical conditions may rarely precipitate acute respiratory failure through involvement of the neurologic system in various ways, including botulism, acute attack porphyrias, EatonLambert syndrome, anticholinesterase intoxication, severe phosphate deficiency, and periodic paralysis. Respiratory care is supportive and similar to that described earlier. The principal challenges are making the diagnosis and instituting appropriate specific therapies.

Acute Exacerbations of Chronic Neuromuscular Respiratory Failure The first recognition of respiratory involvement in a patient with a neuromuscular disease is sometimes occasioned by acute respiratory failure. This is almost invariably precipitated by a respiratory infection. It need not be pneumonia; bronchitis will suffice. The reason is fundamentally mechanical. Resistance to linear airflow through a tube is an inverse fourth-power function. That is to say, if the diameter is reduced by half, the resistance increases 16 times. The small airway edema and mucus accumulation may result in substantial increases in respiratory work. This accounts for the chest tightness felt by the otherwise healthy patient with a lower respiratory infection, but in all but the most severe cases, there is an abundance of respiratory reserve. However, if a neuromuscular disease has reduced function by 60% to 70%, the additional work of breathing may be unsupportable, and acute respiratory failure may occur rapidly. If the underlying disease is ALS, the patient may not yet have a diagnosis. If the patient has a muscular dystrophy, the diagnosis may be known, but the respiratory involvement may be unevaluated or unprepared for. In these cases, the patient often presents in respiratory crisis, and endotracheal intubation and mechanical ventilation ensue. The patient who is fortunate enough to present more subacutely is monitored in a way similar to that described earlier, after spirometry, static inspiratory pressures, oximetry, and arterial blood gases are measured, with a decision to intubate and initiate mechanical ventilation based on similar parameters. Noninvasive ventilation may be attempted, but may not be successful if the patient has no experience or has bulbar involvement, difficulty with secretions, or altered consciousness.72 Mechanical ventilatory support is generally necessary until the infection subsides. With the first episode, the patient may wean from ventilation successfully after standard protocols. If that is not possible, extubation to noninvasive ventilatory support may be attempted. This should be undertaken when all variables are favorable: the patient's general status and strength are improved, infection is under control, secretions are minimal, and the patient is fully alert. If this is not successful, a decision about long-term support and tracheostomy must be made. This does not preclude subsequent attempts to convert to noninvasive ventilation, which may be successful.73 If the patient is already successfully receiving NPPV, the chance of noninvasive management is greatly increased. Over approximately 16 years, no patient with muscular dystrophy in my cohort who was already being managed in this way and who had acute respiratory failure as a result of infection required endotracheal intubation. After admission to the hospital, nasal ventilation is increased to 24 hours daily for the duration of the illness, which is treated with antibiotics and supportive care. The experience in patients with ALS who were

successfully treated was similar, largely because virtually all had intact bulbar function and were doing well with noninvasive support. However, if the patient's condition is deteriorating, endotracheal intubation may be lifesaving. It is very important to discuss and finalize decisions about these kinds of interventions before the onset of an acute illness, particularly for those with ALS. References 1. Martinez FJ, Bermudez-Gomez M, Celli BR: Hypothyroidism. A reversible cause of diaphragmatic dysfunction, Chest 96:1059–1063, 1989. 2. Laroche CM, Mulvey DA, Hawkins PN, et al: Diaphragm strength in the shrinking lung syndrome of systemic lupus erythematosus, Q J Med 71: 429–439, 1989. 3. Rosenow EC, Engel AG: Acid maltase deficiency in adults presenting as respiratory failure, Am J Med 64:485–491, 1978. 4. Moufarrej NA, Bertirini TE: Respiratory insufficiency in adult-type acid maltase, South Med J 86:560–567, 1993. 5. Chandler KW, Rozas CJ, Kory RC, et al: Bilateral diaphragmatic paralysis complicating local cardiac hypothermia during open heart surgery, Am J Med 77:243–249, 1984. 6. Cape CA, Fincham RW: Paralytic brachial neuritis with diaphragmatic paralysis. Contralateral recurrence, Neurology 15:191–193, 1965. 7. Fromm GB, Wisdom PJ, Block AJ: Amyotrophic lateral sclerosis presenting with respiratory failure, Chest 71:612–614, 1977. 8. Loh L, Goldman M, Newsom Davis J: The assessment of diaphragm function, Medicine 56:165–169, 1977. 9. Ambler R, Gruenewald JE: Ultrasound monitoring of diaphragm activity in bilateral diaphragmatic paralysis, Arch Dis Child 60:170–172, 1985. 10. Miller JM, Moxham J, Green M: The maximal sniff in the assessment of diaphragm function in man, Clin Sci 69:91–96, 1985. 11. Celli B, Rassulo J, Corral R: Ventilatory muscle dysfunction in patients with bilateral idiopathic diaphragmatic paralysis: Reversal by intermittent negative pressure ventilation, Am Rev Respir Dis 136:1276–1278, 1987. 12. Glenn WWL, Brouillette RT, Dentz G, et al: Fundamental considerations in pacing of the diaphragm for chronic ventilatory insufficiency: a multicenter study, Pacing Clin Electrophysiol 11:2121–2127, 1988. 13. Redding GJ, Okamoto GA, Guthrie RD, et al: Sleep patterns in nonambulatory boys with Duchenne muscular dystrophy, Arch Phys Med Rehabil 66:818–821, 1985. 14. Baydur A: Respiratory muscle strength and control of ventilation in patients with neuromuscular disease, Chest 99:330–338, 1991. 15. Finder JD, Birnkrant D, Carl J, et al: Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement, Am J Respir Crit Care Med 170:456–465, 2004. 16. Raphael JC, Chevret S, Chastang C, et al: Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy, Lancet 343(8913):1600–1604, 1994. 17. De Troyer A, Borenstein S, Cordier R: Analysis of lung volume restriction in patients with respiratory muscle weakness, Thorax 35:602–610, 1980. 18. Estenne M, Heilporn A, Delhez L, et al: Chest wall stiffness in patients with chronic respiratory muscle weakness, Am Rev Respir Dis 128:1002–1007, 1983. 19. Bach JR: Mechanical insufflation-exsufflation. Comparison of peak expiratory flows with manually assisted and unassisted coughing techniques, Chest 104:1553–1562, 1993. 20. Vianello A, Corrado A, Arcaro G, et al: Mechanical insufflation-exsufflation improves outcomes for neuromuscular disease patients with respiratory tract infections, Am J Phys Med Rehabil 84:83–88, 2005. 21. Ward S, Chatwin M, Heather S, et al: Randomised controlled trial of noninvasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia, Thorax 60: 1019–1024, 2005. 22. Meyer TJ, Hill NS: Noninvasive positive pressure ventilation to treat respiratory failure, Ann Intern Med 120:760–770, 1994. 23. Gomez-Merino E, Bach JR: Duchenne muscular dystrophy: prolongation of life by noninvasive ventilation and mechanically assisted coughing, Am J Phys Med Rehabil 81:411–415, 2002.

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