Respiratory Complications in Neuromuscular Disorders

Diaphragm Paresis/Paralysis

Development of diaphragmatic weakness or paralysis can be insidious (with progressive disorders like Duchenne muscular dystrophy [DMD]) or rapid (such as with trauma or inflammation). Diaphragm weakness can be unilateral or bilateral, and etiology is not always clear. Diaphragm weakness can result from metabolic (hypothyroidism; ), inflammatory (Guillain-Barré syndrome, systemic lupus erythematosus; vanishing lung syndrome; ), or myopathic (DMD, Pompe disease; ; ) causes. It may also be caused by phrenic nerve injury as a result of cardiac surgery ( ), trauma, inflammation (as associated with pneumonia), hereditary neuropathy (Charcot-Marie-Tooth or Dejerine-Sottas, spinal muscular atrophy), or motor neuron disease ( ).

Patients with unilateral diaphragm paralysis are often asymptomatic unless there is underlying lung disease or obesity ( ). 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. 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 relax and the abdominal viscera pulls the diaphragm down by gravity, augmenting inspiration. Physical examination varies from no change in effort but with an elevation of the hemidiaphragm on percussion of the chest to use of accessory muscles in the neck. In the supine position, paradoxical motion can be evident, with the abdomen moving in rather than out with inspiration. Careful percussion of the chest at maximal points of inspiration and expiration will demonstrate 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 amyotrophic lateral sclerosis (ALS) may be associated with pathologic reflexes and fasciculations. Primary underlying diseases, such as lupus, hypothyroidism, and previous trauma, including surgery, should be sought. A recent severe bacterial pneumonia on the ipsilateral side may precede idiopathic cases.

The classic confirmatory diagnostic test is fluoroscopy, during which the patient forcefully sniffs. 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 of normal diaphragmatic function ( ). 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 and is helpful to reduce radiation exposure ( ).

Additional tests include pulmonary function tests, measurement of maximal inspiratory pressure, and diaphragmatic electrodiagnostic studies. Spirometry generally shows a reduction in forced vital capacity (FVC). Plethysmographic total lung capacity is reduced. 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, as this reflects the abdominal musculature, not the diaphragm. Maximum transdiaphragmatic pressure, or P _DImax (the difference between esophageal pressure and gastric pressure, which requires balloon manometry in both organs), is always reduced, usually less than 30 cm H ₂ O. Sniff nasal inspiratory pressure, or SNIP, is a newly described test and is quite easy to perform. This test can be performed in a wide age range and requires little training ( ).

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.

Patients with unilateral diaphragm paralysis may present with a history of sleeping in a chair due to dyspnea while lying flat. Therapy is indicated at the time of diagnosis. Most patients can be treated successfully with noninvasive nocturnal noninvasive ventilation.

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 ( ; ; ).

Muscular Dystrophies

The most common of the hereditary neuromuscular disorders requiring respiratory support is DMD. The young men with this X-linked disease have a relatively similar course, being in a wheelchair full time by roughly 12 years of age and developing respiratory failure by the late teens or occasionally as late as the early 20s. The phases of respiratory dysfunction are predictable and follow through four stages.

Patients in the first stage tend to be ambulatory or only part-time users of wheelchairs. During this stage, there is little respiratory disease but there is a higher incidence of obstructive sleep apnea due to a combination of lingual hypertrophy and decreased upper airway tone ( ). This can be screened by history: snoring is invariably present in those patients with obstructive sleep apnea. Sleep studies are essential in identifying those patients requiring nocturnal positive pressure support in the form of constant positive airway pressure (CPAP) via mask.

The second stage occurs after the patient has become a full-time wheelchair user and is the development of insufficient cough. These patients can be easily identified before the development of symptoms by simple in-office tests including pulmonary function testing, peak cough flow, and measurement of maximal expiratory pressure. As a rule, a peak cough flow in excess of 270 L/min and peak expiratory pressure over 60 cm H ₂ O suggest adequate cough clearance. Values under 270 L/min for peak cough flow should prompt consideration of assisted coughing techniques, particularly mechanically assisted coughing. The goal in frequent pulmonary function testing is to predict those patients at risk for developing pneumonia and therefore prevent the need for hospitalization. Mechanically assisted cough devices can also be used for lung volume recruitment by deeply insufflating the lungs ( ; ; ; ).

The third stage is the development of nocturnal hypoventilation. There is a correlation of inadequate nocturnal ventilation and FVC on spirometry, with a strong association of those patients with FVC less than 30% predicted requiring nocturnal ventilatory support ( ). Consensus recommendation has been for annual screening sleep studies on those patients with FVC less than 50% predicted ( ; ). Often, patients have evidence of sleep disturbance or nocturnal hypoventilation, with frequent awakenings, daytime sleepiness, and morning headaches and even report nightmares of smothering. Morning headaches are characteristic and should be treated with great concern when present on awakening and clearing within 1 hour or less without intervention. These headaches are caused by nocturnal hypercapnia. Sleep studies with initiation of noninvasive positive pressure support by mask interface (bilevel positive pressure) should be titrated to normalize ventilation (CO ₂ level), especially during rapid eye movement sleep. Aggressive management of nocturnal ventilation is also critical to minimize right heart strain due to alveolar hypoxia in these patients who also have cardiomyopathy.

The fourth stage is that of daytime hypoventilation, both awake and asleep. The age in which this develops is quite variable, from mid-teens to mid-20s, and is likely affected by steroid use. This stage can be quite easily diagnosed by measuring end-tidal P co ₂ in the ambulatory setting. A P co ₂ of >45 mm Hg in an awake patient is indicative of CO ₂ retention and daytime respiratory insufficiency. In years past, this had been an indication for placement of tracheostomy, but more frequently, patients have been choosing noninvasive ventilation. This form of ventilation is generally delivered with a set volume delivered via an angled mouthpiece within reach of the patient’s mouth, with a portable ventilator mounted behind the patient’s wheelchair. The mode of ventilation used is triggered by the patient’s inspiratory effort and is delivered as a set tidal volume via a single limb open circuit. This circuit is supported by an adjustable semirigid arm, which holds the mouthpiece just in front of the patient’s mouth. This technique can also allow the patient to breath stack to fully expand the lungs to achieve maximum insufflation capacity, thereby resolving atelectasis, improving airway clearance, stretching the intercostal muscles, and avoiding the development of chest wall rigidity ( ). This technique has been referred to as lung volume recruitment ( ). Mouthpiece ventilation (also referred to as “sip and puff” ventilation) has been used in a broad variety of neuromuscular diseases, including ALS ( ), spinal cord injury, and other myopathic disorders in which there is CO ₂ retention. Critical to success is the ability to understand the technique, and so significant neurocognitive dysfunction is a relative contraindication to mouthpiece ventilation. Intact bulbar function is also necessary since the patient needs to be able to form a seal around the mouthpiece.

Becker muscular dystrophy is a mild form of dystrophinopathy in which the dystrophin gene defect results in a present but reduced-function protein (generally from an in-frame deletion resulting in a shortened protein). These patients follow a course similar to that of DMD, but with each milestone, including the development of respiratory failure, delayed in onset by approximately a decade or more.

The second most common muscular dystrophy requiring ventilatory support is myotonic dystrophy, Type 1. Age of onset is variable 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 progressively 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. Myotonia of the diaphragm is undoubtedly present, but of uncertain significance in the development of respiratory symptoms ( ).

Other hereditary muscular dystrophies (limb-girdle, facioscapulohumeral, Emery-Dreifuss) are far 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 exhaled CO ₂ , should be performed. Arterial puncture is no longer required given the broad availability of exhaled CO ₂ monitors in the ambulatory setting; capillary blood gas is also helpful in assessing for CO ₂ retention. A baseline chest x-ray will be helpful in evaluating subsequent respiratory infections, particularly if there are baseline abnormalities in heart size or in pulmonary parenchyma, spinal structure, or diaphragm. Symptoms of sleep disordered breathing should prompt a sleep study. Symptomatic dysphagia or recurrent pneumonias suggesting aspiration may be evaluated by modified barium swallow or fiberoptic evaluation of swallowing by an otolaryngologist. 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 loss of muscles of chewing and swallowing, gastrostomy placement should be considered. Weight loss may lead to loss of soft tissue on the buttocks and back, making both bed and wheelchair use uncomfortable and placing the patient at greatly increased risk for pressure sores.

Monitoring of patients who are asymptomatic is critical in order to predict those at risk for subsequent respiratory complications prior to a development of a medical crisis. The goal is prevention of illness and hospitalization. Serial monitoring of FVC is helpful in identifying those at risk for nighttime ventilatory failure. Monitoring of peak cough flows will identify those at risk for ineffective cough clearance and, therefore, pneumonia. In later stages of the disease, measuring exhaled CO ₂ will identify those patients developing daytime respiratory failure, even in the absence of overt symptoms. Pulmonary evaluations should be performed at 6-month intervals, or more frequently depending on changes in status and development of new symptoms. Because of the possibility of life-threatening complications of even seemingly minor respiratory infections (discussed later), patients and their caregivers are told to seek care promptly at onset of symptoms.

Pulmonary function tests in these muscular dystrophies ( ) characteristically show restriction, with diminished volumes and flows and a normal-to-elevated ratio of forced expiratory volume in 1 second to FVC. The majority of volume reduction occurs in the measurements that depend on muscle strength. Thus, FVC and its subdivisions are much more reduced than functional residual capacity or residual volume ( Fig. 2.1 ). Most of the reduction is probably the result of muscle weakness, although there is some evidence that there can also be a contribution of chest wall restriction from intercostal muscle fibrosis. As a result, functional residual capacity (determined by the relative elasticity of the lungs and chest wall) may be mildly reduced. Residual volume is increased due to the inability to fully exhale.

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 H ₂ O for men and approximately −90 cm H ₂ O for women, with a broad range. Corresponding values for maximal expiratory pressure, measured from total lung capacity after a full inhalation, are approximately +230 cm H ₂ O for men and +150 cm H ₂ O for women. Values of less than 60 cm for maximum expiratory pressure have been associated with a loss of “flow transients” or “cough spikes” on pulmonary function testing, suggesting inadequate cough clearance ( ).

Respiratory management of patients with muscular dystrophy has been described in several consensus statements, and the reader is referred to these documents ( ; ).

Because the muscles of coughing are weak, use of mechanical insufflation-exsufflation (MI-E) is recommended to improve airway clearance ( ; ; ). These devices rapidly inflate and then deflate the lungs, generating high airway velocities. Pressures are gradually increased as tolerated to achieve maximum pressures of approximately 40–45 cm H ₂ O for expiratory phase; inspiratory pressures for a healthy patient generally are sufficient in the range of 35–45, but these values can be adjusted to comfort and effect. Use of these devices has become widespread since the publication of the 2004 American Thoracic Society consensus guidelines statement on respiratory management of DMD ( ). Interestingly, since the publication of these guidelines, mean survival in DMD has increased by a full decade from 18 to 28 years ( ). Use of the insufflation phase for lung volume recruitment may be of value to resolve asymptomatic atelectasis and to help stretch the intercostal muscles and avoid development of a rigid chest wall ( ; ; ).

Evidence of daytime hypoventilation is generally considered an indication for initiation of 24-hour ventilatory support. These factors include daytime hypercapnea (as documented in clinic visit by end-tidal capnography) and nocturnal hypoventilation (as demonstrated by sleep study). Longitudinal experience of multiple groups is unequivocal in showing that noninvasive positive pressure ventilation (NPPV) improves symptoms, quality of life, and longevity ( ; ) 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 ( ).

The most common approach to managing daytime respiratory failure with CO ₂ retention is use of a mouthpiece ventilator ( Fig. 2.2 ), which requires intact bulbar muscle function and the intellectual capacity to understand use of this device. This approach has been greatly aided by the development of lightweight portable ventilators ( Fig. 2.3 ), which can be mounted behind the wheelchair. The angled mouthpiece is held in place adjacent to the patient’s lips by an adjustable arm. The ventilator is set to deliver a set tidal volume, usually in the range of 750–1000 mL, when triggered by the patient’s inspiratory effort (assist control mode).

Nasal pillows interface is occasionally preferred when mouthpiece ventilation is not well tolerated. Placement of a tracheostomy remains an option for patients who do not tolerate noninvasive ventilation.

For nighttime ventilation, interface selection is critical to success. It is more than a matter of individual choice and comfort: if the mask cannot be tolerated, it will not be used, and the patient will remove it in the night and have respiratory failure. Interfaces can be nasal, oronasal, full-face mask, or intranasal ( Figs. 2.4 and 2.5 ). It may be helpful to have more than one interface to alternate pressure points.

Mask interfaces for noninvasive ventilation are designed with holes for air leak. Combined with expiratory positive pressure, the holes minimize CO ₂ 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.

Bilevel positive airway pressure devices, originally designed for treatment of sleep apnea, have evolved into more sophisticated ventilators and have largely supplanted volume ventilators for noninvasive management. If pressure mode is chosen, pressures necessary to provide adequate tidal volume and rest the respiratory muscles must be chosen. The most frequent reason for unsatisfactory results from bilevel positive pressure is inadequate inspiratory pressures; the goal in the neuromuscularly weak patient is high-span bilevel positive pressure support. In other words, it is the span (the difference between inspiratory pressure and expiratory pressure) that determines the tidal volume. Expiratory pressure airway pressure (EPAP) is used for the purpose of purging carbon dioxide from the mask; 4 to 5 cm H ₂ O is generally adequate. Newer modes of ventilation that can be delivered to approximate a volume ventilator (without requiring an actual volume ventilator) use a technology referred to as “average volume assured pressure support.” This is a combination of pressure-limited and volume-limited modes of ventilation designed to reduce barotrauma and help deliver a single tidal volume.

Tidal volumes and respiratory rates (generally as back-up 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, ideally in a sleep laboratory. The nighttime ventilator mode is usually assist-control, although intermittent mandatory ventilation with pressure support is a comfortable alternative. Oxygen administration during this process should be avoided, since supplemental oxygen will mask the desaturation that results from hypercarbia and will also suppress hypoxic drive.

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 optimal interface selection, strap adjustment, and appropriate support of ventilator tubing ( Fig. 2.6 ). This 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 chin strap. 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.

Once home ventilation has been initiated, the patient is seen and evaluated after 3 to 4 weeks. With few exceptions, daytime P co ₂ will have diminished to less than 50 mm Hg. 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 P co ₂ ( ; ; ).

Thereafter, the patient is seen regularly at intervals of 3 to 6 months. Early on, increases in daytime P co ₂ are often caused by reductions in nocturnal use and will respond to increases. Over several years, it will be necessary to increase the 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. Current portable ventilators can be mounted to or hung from the back of a wheelchair.

The choice of noninvasive ventilation versus tracheostomy is a personal one, made after consideration of the risks and benefit of each approach. In the severely weak patient, disconnection from the noninvasive ventilator interface is a very real and life-threatening risk, and thus, these patients require a caregiver nearby at all times, with monitoring via continuous pulse oximetry in sleep. For those who prefer a nasal interface over a mouthpiece interface (as can be necessary with bulbar muscle weakness), continuous use can lead to skin breakdown. Placement of a tracheostomy will ensure a stable and reliable airway, but with some short-term pain, risks of anesthesia in a patient with possible cardiomyopathy, and risks of tracheitis and bleeding. This choice is ultimately that of the patient and family, and a well-informed pulmonologist should be able to present a balanced approach to help them with this critical decision.

If a decision is reached to choose 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. Flexible silicone tracheostomy tubes (such as Bivona® Smiths Medical) are generally preferred to the rigid ones as they are less traumatic to the upper airway and generally better tolerated than rigid tracheostomy tubes.

Although it is possible for a patient to produce speech while ventilated with an uncuffed tube alone, the speech pattern is noncontinuous and occurs only during expiration, 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. 2.7 and 2.8 ). 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. Tracheostomy further impairs the ability to cough in these patients who already have inadequate cough clearance due to weakness, and suctioning is necessary. Family members must be taught proper technique. Adequate nutrition is also important. 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 or increase oral feedings; given the normal expiratory flow allowed by a one-way valve, aspiration risk is reduced.

Spinal Cord Injury

Spinal cord injury above C4 often is associated with paralyzed diaphragms as well as paralysis of the scalene, intercostal, and abdominal muscles but 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 phrenic nerves 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, thereby impairing cough clearance while preserving ventilation. 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 ( ). For patients with very high lesions and demonstrable phrenic function by nerve conduction studies and diaphragmatic electromyogram, diaphragm pacing may be an option ( ).