Abstract
In 2010, Care Considerations for Duchenne Muscular Dystrophy, sponsored by the Centers for Disease Control and Prevention, was published in Lancet Neurology, and in 2018, these guidelines were updated. Since the publication of the first set of guidelines, survival of individuals with Duchenne muscular dystrophy has increased. With contemporary medical management, survival often extends into the fourth decade of life and beyond. Effective transition of respiratory care from pediatric to adult medicine is vital to optimize patient safety, prognosis, and quality of life. With genetic and other emerging drug therapies in development, standardization of care is necessary to accurately assess treatment effects in clinical trials. This revision of respiratory recommendations preserves a fundamental strength of the original guidelines: namely, reliance on a limited number of respiratory tests to guide patient assessment and management. A progressive therapeutic strategy is presented that includes lung volume recruitment, assisted coughing, and assisted ventilation (initially nocturnally, with the subsequent addition of daytime ventilation for progressive respiratory failure). This revision also stresses the need for serial monitoring of respiratory muscle strength to characterize an individual’s respiratory phenotype of severity as well as provide baseline assessments for clinical trials. Clinical controversies and emerging areas are included.
- CO2 —
- carbon dioxide
- DMD —
- Duchenne muscular dystrophy
- FVC —
- forced vital capacity
- OSA —
- obstructive sleep apnea
- SpO2 —
- pulse oxygen saturation
With progressive loss of muscle strength, individuals with Duchenne muscular dystrophy (DMD) are at risk for respiratory complications, including ineffective cough, lower respiratory tract infections, nocturnal hypoventilation and/or obstructive sleep apnea (OSA), and ultimately, daytime respiratory failure.1–7 Immobility, scoliosis, heart failure, malnutrition, and dysphagia with aspiration also may contribute to progressive respiratory dysfunction.8
When untreated, patients experience dyspnea and are at risk for prolonged hospitalizations and death from mucus plugging, severe pneumonia, or respiratory-induced cardiac arrhythmias.1–7,9
The aim of respiratory care is to prevent these potential complications and manage them in a timely way. A structured, anticipatory approach to respiratory management requires monitoring respiratory muscle strength as well as initiating lung volume recruitment, assisted coughing, nocturnally assisted ventilation, and eventually daytime ventilatory support. These therapies have been shown to improve quality of life and prolong patient survival.9–17
Respiratory management is a multidisciplinary endeavor. In addition to home caregivers, the care team should include a physician and respiratory therapist (or physical therapist, in some health care systems) who can perform pulmonary function testing and sleep studies and are skilled in managing lung volume recruitment, manual and mechanically assisted coughing, noninvasive ventilation with associated interfaces, tracheostomies, and mechanical ventilators.
Objectives
The 2018 DMD Care Considerations, sponsored by the Centers for Disease Control and Prevention, seeks to preserve a fundamental strength of the 2010 version of the guidelines, that is, reliance on a limited number of respiratory tests to guide patient assessment and management.7,18,19 These tests are, within the limitations of the existing scientific literature, well studied, clinically relevant and reproducible, and can be measured by using only a few pieces of widely available and relatively inexpensive equipment, namely, a spirometer, a peak flowmeter, a manometer, and a pulse oximeter. By optimizing the practicality and applicability of our core recommendations, we seek to minimize the barriers to achieving the highest level of DMD respiratory care for clinicians in all practice venues, including those with limited access to professional and physical resources.
This revision also contains new recommendations not found in the 2010 Care Considerations document. In the current version, we simplify the criteria for initiating assisted coughing and assisted ventilation and emphasize noninvasive modalities of ventilation. We recommend respiratory interventions at a somewhat higher level of pulmonary function compared with the 2010 criteria and endorse using similar criteria for initiating both assisted coughing and assisted ventilation, thereby advocating for simultaneous, rather than sequential, initiation of these key therapies. With this strategy, we seek to emphasize the need for anticipatory respiratory management before patients develop complications.
Specific Core Recommendations
Ambulatory Stage
While ambulatory, individuals with DMD should learn pulmonary function testing and, with their caregivers, be educated about assessing and managing respiratory complications. Starting at 5 to 6 years of age, annual measurements of seated forced vital capacity (FVC) should be made, to train patients in spirometry and to start assessing each patient’s course of pulmonary function over time (Fig 1). Serial monitoring of pulmonary function is critical because FVC will eventually decline silently (in the absence of dyspnea) in nonambulatory patients. In general, FVC increases with growth until the loss of ambulation, at which point FVC will sequentially peak, plateau, and then deteriorate over time.20–22 Although this general description is accurate, the age at peak FVC, the level of the maximal FVC value, and the subsequent rate of deterioration in FVC can all vary greatly among individual patients, even among patients who share the same dystrophin mutation (Fig 2).7,23,24 Thus, serial measurement of FVC is essential because it allows clinicians to assess the respiratory course of individual patients over time, characterizing their personal respiratory trajectory and phenotypic severity.
Care considerations for respiratory management of DMD patients by stage of disease. The components of pulmonary management for patients during each of the 3 major stages of DMD are described in this figure: ambulatory, early nonambulatory, and late nonambulatory. (Reproduced with permission from Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopedic management. Lancet Neurol. 2018;17[4]:348. See that text for additional details.)
FVC versus age for 2 brothers with the same genotype. How pulmonary function can vary even among individual patients with the same genotype is shown in this figure. One brother has a favorable respiratory phenotype, with FVC preserved over time, whereas the other brother has a more severe phenotype, with a lower value for peak FVC, followed by more rapid decline. (Reprinted with permission from Birnkrant DJ, Ashwath ML, Noritz GH, et al. Cardiac and pulmonary function variability in Duchenne/Becker muscular dystrophy: an initial report. J Child Neurol. 2010;25[9]:1111.)
It is important to also consider the respiratory implications of glucocorticoid therapy. Use of glucocorticoids can prolong the period of ambulation and preserve pulmonary function in individuals with DMD.25 However, weight gain is a common side effect. As a result, OSA is the most common form of sleep-disordered breathing among steroid-treated patients in the ambulatory and early nonambulatory stages of DMD, affecting patients as young as age 12 years. OSA is positively correlated with BMI.26 Sleep evaluations with capnography are indicated for individuals with sleep-disordered breathing symptoms and are discussed in more detail in the sections that follow.
To prevent or minimize respiratory illnesses, individuals should receive immunization with the inactivated influenza vaccine yearly and pneumococcal vaccines (including pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine) according to the recommended schedule. Guidelines for the timing and frequency of these vaccines are available from the Centers for Disease Control and Prevention27 and from the Parent Project Muscular Dystrophy.28
Early Nonambulatory Stage
Respiratory complications and the need for respiratory interventions primarily occur after the loss of independent ambulation. Respiratory assessments and interventions indicated during this stage are shown in Fig 1.
When FVC is ≤60% predicted, lung volume recruitment is indicated to preserve respiratory system compliance. Lung volume recruitment is achieved with the use of a self-inflating manual ventilation bag or mechanical insufflation–exsufflation device applied once or twice daily29–32 (see protocols for this procedure on the CANVent Web site: http://canventottawa.ca/EducationModules/Phase/2). Some individuals with DMD require surgery for progressive scoliosis. Specific guidelines have been published addressing the pre- and postoperative respiratory care of these patients.33,34 Preoperative polysomnography should be considered for individuals who are cognitively impaired and unable to reliably perform pulmonary function testing.
Late Nonambulatory Stage
Individuals with DMD eventually develop a weak, ineffective cough associated with chest congestion from retained respiratory secretions, putting them at risk for atelectasis, pneumonia, ventilation-perfusion mismatch, and progression to respiratory failure when they acquire what would otherwise be a mild respiratory tract infection. Therefore, before the onset of these complications, the next respiratory intervention is to initiate manual and/or mechanical cough assistance, the criteria for which are shown in Fig 1.35–52 For videos and practical guidance, see the CANVent Web site: http://canventottawa.ca/EducationModules/Phase/2.
When assisted coughing is begun, a pulse oximeter should be available in the home to aid clinical assessment because mild hypoxemia (pulse oxygen saturation [Spo2]: <95% in room air) is an indication to increase the frequency of assisted coughing. Such a strategy can be used to prevent mucus plugging, atelectasis, and pneumonia as well as hospitalization8 (see Supplemental Fig 3, Duke Airway Clearance protocol). During acute respiratory illnesses, antibiotic therapy should be added for patients who have 3 of the following 5 clinical signs of pneumonia: fever, elevated white blood cell count or C-reactive protein level, sputum production, a pulmonary infiltrate on the chest radiograph, or hypoxemia or respiratory distress.53
Later in this stage of the disease, individuals require assisted ventilation during sleep to prolong their survival. When vital capacity falls below 1 L, mean survival is just 3.1 years without the use of assisted ventilation.54
Indications for nocturnal assisted ventilation are listed in Fig 1.7,26,33,55–58 Nocturnal assisted ventilation is indicated when individuals with DMD have abnormal sleep studies. These studies include overnight oximetry, combination oximetry–capnography, and polysomnography with capnography. The benefit of capnography is that it can be used to detect changes in alveolar ventilation that remain undetected with oximetry alone (eg, when the patient’s Spo2 is on the flat portion of the oxyhemoglobin dissociation curve). For symptoms of sleep-disordered breathing, patients should have sleep studies as often as annually, when such studies are available. In addition to the criteria in Fig 1, nocturnally assisted ventilation is indicated if sleep study results show any of the following: end-tidal or transcutaneous carbon dioxide (CO2) >50 mm Hg for ≥2% of sleep time, a sleep-related increase in end-tidal or transcutaneous CO2 of 10 mm Hg above the awake baseline for ≥2% of sleep time, Spo2 ≤88% for ≥2% of sleep time or for at least 5 minutes continuously, or an Apnea–Hypopnea Index ≥5 events per hour.59,60 For case examples and guidance on monitoring for signs and symptoms of respiratory failure, see the CANVent Web site at http://www.ohri.ca/NIVAM/Default.aspx?SlideID=457.
Even in DMD patients with OSA, continuous positive airway pressure therapy should be avoided because individuals with DMD will eventually require assisted ventilation to manage hypoventilation. Noninvasive ventilation also can be used during and after procedures involving sedation or anesthesia and, in conjunction with assisted coughing, to successfully extubate individuals who are mechanically ventilated for acute respiratory failure (see Supplemental Fig 4, Duke Neuromuscular Patient Extubation Protocol).61
The process of extending nocturnally assisted ventilation into daytime and, ultimately, 24-hour-per-day ventilation will often be guided by the patient himself. With progressive respiratory muscle weakness, individuals become increasingly dyspneic and tachypneic while awake, despite nocturnally assisted ventilation. Indications for daytime assisted ventilation all reflect symptomatic hypoventilation (Fig 1). Individuals with DMD who have very low FVCs (eg, <680 mL6) are at particular risk of awake hypoventilation.6
Progression toward continuous use of a noninvasive or invasive ventilator means that the individual with DMD is essentially using the device for life support and should be provided with a back-up ventilator and a manual resuscitation bag in case the primary ventilator malfunctions. In addition, several batteries and/or a generator are needed to run the ventilation device during a power outage, and batteries are needed for mobility and travel. Arrangements should be made for attaching the ventilation device to the patient’s wheelchair, so that the patient can achieve mobility, optimizing his quality of life.
In persons with DMD, hypoxemia is usually caused by hypoventilation and/or ventilation–perfusion mismatch related to mucus plugging. We therefore strongly caution against the use of supplemental oxygen therapy without simultaneous use of assisted ventilation and assisted coughing. With oxygen therapy alone, the underlying causes of hypoxemia remain untreated; hypoventilation and respiratory acidosis can occur and respiratory drive may be impaired.62 In contrast, when accompanied by assisted ventilation and assisted coughing, oxygen therapy can be used safely to maintain adequate oxygenation during acute respiratory illnesses, especially when blood CO2 levels are monitored.
Clinical Controversies
The issue of whether patients with DMD should be ventilated by tracheostomy or noninvasively, such as with a nasal mask or pillows, is a clinical controversy that evokes strong opinions among experts in the field. Some centers initiate assisted ventilation noninvasively and then transition patients to tracheostomy as their pulmonary function declines (eg, when the patient needs 16 hours per day or more of assisted ventilation). At other centers, patients receive a tracheostomy as soon as they start assisted ventilation.63,64 However, the use of noninvasive assisted ventilation for up to 24 hours per day is supported in a growing body of literature, as well as in clinical experience.11,16,65,66 When it is well tolerated, our panel strongly recommends noninvasive assisted ventilation instead of tracheostomy.67
During sleep, many individuals with DMD default to their noninvasive ventilator’s back-up rate of breathing. It is, therefore, essential for DMD patients to use noninvasive ventilators that can function in both spontaneous and timed modes, that is, devices that ensure a minimum breathing rate, triggered by a timer, to prevent apnea. Options for 24-hour-per-day noninvasive ventilation include daytime mouthpiece or “sip” ventilation using a portable volume ventilator during wakefulness and switching to a bilevel device during sleep68 (see the sip protocol at http://canventottawa.ca/Nivam/Phases/4.aspx). Twenty-four–hour-per-day nasal ventilation with a bilevel device alone can also be well tolerated. Nevertheless, the initiation of assisted ventilation via tracheostomy may be preferable for some patients with DMD, and indications for tracheostomy are listed in Fig 1.69 It is important to recognize that some patients who begin assisted ventilation noninvasively may eventually require “rescue tracheostomy” in the setting of critical illness (eg, during a hospitalization) when they require intubation and subsequently fail several attempts to be extubated to noninvasive ventilation.59,61,70 This clinical scenario may become more common as individuals who have used noninvasive ventilation for a decade or more live into their 30s and beyond.9 Choosing the best mode of assisted ventilation for individuals with DMD is a complex issue. Issues to consider include the following: the clinical course of the patient, individual patient preference, the usual practices and skills of the patient’s clinicians, local care standards, and the availability of needed resources, including skilled home caregivers. Currently, no known predictors exist to identify individuals with DMD who will eventually fail noninvasively assisted ventilation. Such predictors would be useful if they allowed patients who are ventilated noninvasively to undergo elective tracheostomy while they are healthy, avoiding the risks and morbidity of rescue tracheostomy in the setting of critical illness. Regarding risk factors, noninvasive respiratory aids are especially challenging to use when individuals with advanced DMD develop acute respiratory illnesses and when they have chronic difficulty handling their oropharyngeal secretions due to swallowing dysfunction.
Emerging Areas That Require Additional Research and Validation
In the recommendations above, we describe a set of core diagnostic tests and therapeutic interventions that are necessary for optimal respiratory evaluation and treatment of patients with DMD. Various other diagnostic tests and therapeutic techniques also may be appropriate for use in selected patients; they have potential clinical use and may be appropriate for specialty clinics, but they require further study and validation. These tests include the following: forced expiratory volume in 1 second, peak expiratory flow rate, sniff nasal inspiratory pressure, inspiratory flow reserve, and rapid shallow breathing index. Both the potential use and limitations of these tests were discussed in a recent workshop and related publication.71 Additional emerging diagnostics that warrant further research include serial measurement of the following: slow vital capacity, maximum insufflation capacity, the maximum insufflation capacity–FVC difference, supine FVC, assisted cough peak flow and highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow and V'I,max [FVC]), optoelectronic plethysmography, measurements of diaphragmatic compound muscle potential, and respiratory impedance.72–78 When available, supine FVC monitoring can add important information because, with progressive diaphragmatic weakness, the difference between seated and supine FVC increases, and patients experience nocturnal symptoms and declining pulmonary reserve.72,73 Additionally, once they are validated for the DMD population and have been shown to have predictive value for initiating respiratory therapies, the results of questionnaire tools, such as the modified Borg score, have the potential to be used to supplement pulmonary function testing.74,75
Areas with significant therapeutic implications for respiratory health that require additional research include the following: the potential benefits of respiratory muscle training, the relationship between nutrition and respiratory muscle strength, the optimal timing for gastrostomy placement, and the contribution of chronic aspiration to the respiratory complications of DMD.76–81 Other potentially beneficial therapies include high-frequency chest oscillation, intrapulmonary percussive ventilation, and biphasic cuirass ventilation or airway clearance.82,83 Another area that merits further research is the potential for improved mucus clearance and assisted ventilation devices to prevent cardiac death by eliminating fatal arrhythmias induced by transient hypoxemia and/or acidosis caused by mucus plugging or hypoventilation.10
Future Directions
Genetic and molecular therapies are being developed for DMD at an unprecedented rate.84 Because respiratory complications are major determinants of survival and quality of life, it is critically important to consider the best methodology for evaluating the respiratory effects of these new therapies.
Use of Respiratory Devices During Clinical Trials of Emerging Therapies
Contemporary methods of respiratory management, such as those endorsed in the Specific Core Recommendations section of this article, have been used to prolong patient survival. Respiratory care in which these methods are employed should, therefore, be specified in the methodology of clinical trials of emerging DMD therapies. This includes initiation of lung volume recruitment, assisted coughing, and assisted nocturnal and daytime ventilation. At present, adherence with best practice guidelines appears to be lacking.63,84–86 Adherence to respiratory guidelines like those in this statement, as well as standardized approaches to cardiac management and treatment with glucocorticoids, is needed to minimize variability of care, improve patient outcomes, and assess the effects of new treatments.
Development of Clinically Meaningful Pulmonary Outcome Measures
FVC as a Primary Outcome Measure
The development of reproducible and clinically meaningful pulmonary outcome measures will be essential to assess the efficacy of new therapies. For a detailed discussion, the reader is referred to the “Pulmonary Endpoints in Duchenne Muscular Dystrophy” workshop publication.71 Key recommendations include the use of seated FVC as the primary pulmonary outcome measure. Forced expiratory volume in 1 second, maximum inspiratory pressure, maximum expiratory pressure, peak cough flow, peak expiratory flow rate, and sniff nasal inspiratory pressure are considered to be secondary end points, pending further validation. Tests of seated FVC should be performed by a technician with suitable training and validated by using American Thoracic Society criteria that have been modified for patients with DMD.21
The Natural History of FVC in Patients With DMD: Pulmonary Phenotypic Variability
In DMD patients, the pattern of FVC over time is typically composed of 3 stages: while the patient is ambulatory, FVC rises annually; during the early nonambulatory stage, FVC plateaus and remains constant for several years; and during the late nonambulatory stage, FVC progressively declines each year until death. In theory, this pattern should allow for prediction of an individual patient’s respiratory course over time. However, pulmonary function can vary significantly among individual patients, even when the patients have identical dystrophin mutations, such as brothers with DMD.7,23,24 For example, in Fig 2, data are shown from 2 brothers with the same mutation who have highly discordant pulmonary function.87 The poor correlation between dystrophin genotype and pulmonary phenotype makes it difficult to predict the pulmonary course of an individual patient on the basis of genotype alone. Pulmonary outcome measures must be viewed in the context of each individual’s expected course of pulmonary function over time. For example, when evaluating the effect of a therapy on a particular patient, it is necessary to know if the patient is in the rising, plateauing, or declining stage of FVC. In addition, it is necessary to know the patient’s respiratory phenotype (FVC trajectory over time), including the expected level of the patient’s peak FVC, the age at which he will attain peak FVC, and the expected rate of subsequent FVC decline. Without this information, preservation of pulmonary function over time, for example, could be falsely attributed to the effect of a new therapy, rather than the patient’s favorable respiratory phenotype. Because respiratory phenotypic variability is common, results from studies in which researchers examined the effect of new therapies on pulmonary function in aggregate (ie, using pooled FVC data, without regard for each patient’s respiratory stage and respiratory phenotype) will be confounded by the subjects’ variable respiratory stages and phenotypes.
Identification of a patient’s respiratory stage and phenotype involves major challenges, including the need for serial measurement of pulmonary function over time and categorization of the severity of a patient’s respiratory phenotype early in the course of his disease, when new therapies are likely to be initiated. Humbertclaude et al20 found that corticosteroid-naïve boys who lost ambulation before age 8 years had a more severe respiratory phenotype, characterized by a lower peak FVC, which occurred at a younger age and was followed by a more rapid decline compared with patients who remained ambulatory longer. Early predictors of a patient’s long-term respiratory course and phenotype, like age at loss of ambulation, may turn out to be critically important for the evaluation of new DMD therapies.
Proposed Criteria for Assessing the Effect of New Therapies on FVC
The committee endorses that a therapy for DMD is beneficial to the respiratory system if use of that therapy results in a rise in the patient’s FVC that is larger than predicted (when the patient is in the rising stage of pulmonary function), in an unexpectedly prolonged stabilization of the patient’s FVC (when the patient is in the plateau stage of pulmonary function), or in a fall in the patient’s FVC that is smaller than predicted (when the patient is in the declining stage of pulmonary function). In addition, the committee recommends that the absolute value of a patient’s FVC measurements be interpreted in the context of his pulmonary phenotypic severity, including the expected level of his peak FVC, the age at which his peak FVC should occur, and the subsequent course that the patient’s FVC is expected to follow.
Cardiopulmonary Interactions and Phenotypic “Disconnects”
Finally, it is important to understand how pulmonary outcome measures relate to patient survival. Causes of death in contemporary DMD populations have shifted from pulmonary to cardiac complications. This observation was confirmed in a recent study in which authors suggested that when DMD patients are treated with assisted ventilation according to current guidelines, then cardiac function is the main determinant of their survival.9 Additional evidence suggests that individual patients may have a phenotypic disconnect between their respiratory and cardiac function. For example, in the study cited above, prolonged survivors of DMD had good heart function but poor pulmonary function. Patients who experienced early death had the opposite: poor heart function and good lung function. This variable phenotypic expression by different body systems may be caused by genetic modifiers that preferentially affect cardiac or respiratory (ie, skeletal) muscle.88,89 With these observations, it is suggested that pulmonary outcome measures may not be directly related to patient survival. For example, if an individual patient has a detrimental genetic modifier that preferentially affects cardiac muscle, then a therapy that improves skeletal muscle strength, and thus pulmonary function, may not prolong that patient’s survival because that patient is likely to die of progressive cardiomyopathy. Authors of studies of emerging therapies should not equate improved pulmonary function with improved patient survival because in a subset of patients, cardiac function will be the main determinant of their survival. Instead, it is necessary to examine both the pulmonary and cardiac function of each individual patient over time to assess the effect of new therapies on his survival.
Footnotes
- Accepted July 26, 2018.
- Address correspondence to Daniel W. Sheehan, PhD, MD, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 955 Main St, Room 7179, Buffalo, NY 14203. E-mail: dws9{at}buffalo.edu
The guidelines or recommendations in this article are not American Academy of Pediatrics policy and publication herein does not imply endorsement.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported in part by Cooperative Agreement NU38OT000167, funded by the Centers for Disease Control and Prevention.
POTENTIAL CONFLICT OF INTEREST: Dr Birnkrant has United States and international patents and patent applications for respiratory devices; he is also a former consultant to the Hill-Rom corporation. Dr Benditt is a consultant for (and has stock options in) Ventec Life Systems; the other authors have indicated they have no potential conflicts of interest to disclose.
References
- Copyright © 2018 by the American Academy of Pediatrics
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