Management of respiratory complications and rehabilitation in individuals with muscular dystrophies: 1st Consensus Conference report from UILDM - Italian Muscular Dystrophy Association (Milan, January 25-26, 2019).

Respiratory complications are common in the patient with muscular dystrophy. The periodic clinical and instrumental respiratory evaluation is extremely important. Despite the presence in the literature of updated guidelines, patient associations often report lack of knowledge of these pathologies, particularly in peripheral hospitals. The purpose of this work, inspired by the Italian Muscular Dystrophy Association (UILDM) is to improve management of respiratory problems necessary for the management of these patients complex. To this end, the main items that the specialist can meet in the follow-up of these pathologies have been analyzed and discussed, among which the respiratory basal evaluation, the criteria of adaptation to non-invasive ventilation, management of bronchial secretions, situations of respiratory emergency, indications for tracheostomy and the subject of advance directives of treatment (DAT). ©2021 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.

Introduction

Even though the lungs are not directly involved in the disease process, respiratory problems are common in neuromuscular disease (NMD) patients [1,2]. Weakness of inspiratory and expiratory muscles causes decreased ability to expand the lungs and impairs alveolar ventilation leading to low oxygen and high carbon dioxide blood levels [3]. Moreover, due to expiratory muscle weakness secretion management is also impaired because of ineffective expiratory flow during cough; saliva and mucus may accumulate in the upper airways and favour local infections, which may then propagate to lower respiratory tract and the lungs [4].

The extent to which respiratory involvement occurs and the pattern of the respiratory tests may change according to baseline disease and its progression. A number of diseases such as Duchenne Muscular Dystrophy (DMD) show a slowly progressive disease course and respiratory involvement occurs later on, in the advanced phases of the disease. In other diseases such as Facio-Scapolo-Humeral Dystrophy, acute respiratory insufficiency may be the presenting symptom [5]. Moreover, other diseases, such as Myotonic Dystrophies (DM), predominantly show breathing disorders during sleep, which may disrupt diurnal gas exchange and aggravate centrally-driven symptoms such as excessive daytime sleepiness [6].

Standards of care and care recommendations for respiratory management are now available for DMD [7-9] and DM1 [10] where death occurs primarily due to respiratory insufficiency and cardiac problems [11-14]. This means that clinical centre neurologist and/or pulmonologist may have access to theoretical (pathophysiology) and practical (tests and parameters) information to manage NMD patients at best. However, since muscle disorders are rare, a doctor may happen to manage a very limited number of patients in his/her professional career. In addition, the quality of pulmonary function test and patients’ cooperation highly depend on expertise of the technician performing the examination. Finally, access to specialized respiratory centres may be difficult for NMD patients and their families, causing delayed screening and follow-up assessment.

Finally, as research progresses and new treatments for respiratory complications become available, patient and family expectations increase: for this reason, it is crucial that, all patients may be given the possibility to timely access novel respiratory therapies/devices in. Implementation and adherence to standards of care will slow down disease progression and will give the opportunity to include more patients in clinical trials.

The aim of our study was to describe standards of care for the management of respiratory complications in NMD patients and address some specific issues which are still a matter of controversy.

Materials and methods

Participants

Thirteen pulmonologists, 1 intensivist, 1 paediatrician, 1 psychologist and 2 respiratory physiotherapists with experience in respiratory care of paediatric and adult neuromuscular patients, from 16 different Italian sites, met in Milan to focus on the practical issues of respiratory management in muscular dystrophies in light of the existing standards of care for muscular dystrophies such as DMD and DM. One neuromuscular specialist was also included to integrate the respiratory clinical experience with disease-specific neuromuscular features and representatives from medical groups such as AIPO (Associazione Italiana Pneumologi Ospedalieri), SIP (Società Italiana Pneumologia), SIMRI (Società Italiana Medicina Respiratoria Infantile) as well as a patient representative were also present.

Methods

The method was inspired by the US NIH Consensus Program (http://consensus.nih.gov) and adapted from the Methodological Handbook of the Italian National Guideline System [15]. This was the first Consensus Conference organized by the Italian muscular dystrophy association (UILDM). All activities were completed between September 2018 and April 2019. Planning and execution were carried out in 4 stages: (1) assignment, (2) scoping, (3) assessment, and (4) the consensus conference itself. The project included 4 workgroups (Box 1a).

DMD Standards of care implementation survey

In order to assess the level of implementation of respiratory SoC at each of the sites, a survey addressing each item described in the DMD SoC documents was used and given a score from 0 to 2, where 0 indicated that specific aspects were not carried out as described, 1 indicated that the recommendations were only partially addressed as described and 2 indicated that SoC recommendations for that specific item were fully covered. The results of the survey, described in Figures 1-3), showed that sleep studies and specifically nocturnal oximetry and/or capnography and polysomnography were only performed at some sites and, therefore, were not implemented as they should have. In addition, the assessment of maximal inspiratory and expiratory pressures (MIPs and MEPs) was not performed in the more advanced stages of the disease.

Consensus Conference methods Workgroups.

Scientific Committee (4 members): it planned and organized the whole project, nominated the Technical Committee and Workgroup members, chose the questions to be answered by the Workgroups, established the methods and rules of the Consensus Conference and chaired the Consensus Conference.

Technical Commettee (9 members): performed the systematic review with evidence mapping and assisted with defining questions: experts (16 members): synthesized and integrated information, provided shared answers to the proposed questions, and presented their findings during the Consensus Conference.

Consensus Development Panel (8 members): established the reviewing and presentation procedures and provided the final evaluation.

1 Candiani G, Colombo C, Daghini R, et al. Manuale metodologico: come organizzare una conferenza di consenso [online]. Rome: Istituto Superiore di Sanità, Sistema Nazionale Linee Guida SNLG; 2009 (http://www.psy.it/wp-content/uploads/2018/02/Manuale-Metodologico-Consensus.pdf).

Outcomes and endpoints

The overall aim of the workshop was to define baselines and follow-up respiratory assessments for children and adults affected by muscular dystrophy, to raise awareness among health professionals working in the acute settings that a specific approach is required for patients with muscular dystrophies having acute respiratory problems, while also providing caregivers with a practical guidelines for respiratory care. Specific aims of the project were: (i) define respiratory tests and procedures to be performed at baseline and at follow-up for all patients; (ii) determine criteria for starting non-invasive ventilation (NIV); (iii) provide indications for tracheostomy (IMV); (iv) define a protocol to manage acute respiratory insufficiency;(v) describe secretion management protocols; (vi) address end-of life protocols.

Unanimous consent was required to approve the care recommendations, protocol or pathway of care. In case of uncertainty, the panel agreed to declare that no consensus was reached and that further data were needed to define management for that specific aspect.

Respiratory management in patients with muscular dystrophies

Muscular dystrophies are characterized by progressive loss of skeletal muscle mass and progressive muscle weakness. In general, for most of them, respiratory decline becomes more obvious when patients lose ambulation. Weakness of the expiratory muscles causes an ineffective cough while weakness of the inspiratory muscles and scoliosis contribute to the restrictive ventilatory deficit, leading to hypoventilation, initially only at night-time and subsequently, even during the day [16].

a. Respiratory Core data set

Baseline assessments

Look for symptoms of respiratory involvement such as those suggestive of hypoventilation (tiredness, shortness of breath, morning headaches, fragmented sleep, excessive daytime sleepiness, concentration difficulties) and look for signs of pulmonary impairment (thoracic deformities, facial dysmorphism or paradoxical breathing, abdomen and thorax asynchronous movements suggestive of respiratory fatigue [17].

Test for respiratory function including sitting FVC both as an absolute value and as a percentage of the predicted value; maximal inspiratory and expiratory pressures (MIP, MEP), expiratory peak cough flow (PCF). Assessment of sleep-related breathing disorders (SRBD) such as Obstructive Sleep Apnea Syndrome (OSAS) with nocturnal oximetry or cardio-respiratory polygraphy. Additional tests that can be performed are end-tidal or transcutaneous partial pressure of carbon dioxide and arterial blood gas analysis in adults. These tests should be performed if SpO2 spot < 95% at RTP (Box 1).

Treat with air stacking exercises if FVC is < of 60% of predicted value using a self-inflating manual ventilation bag (AMBU bag) or mechanical insufflation-exsufflation device twice a day [18].

b. Follow-up assessments

The progression of respiratory involvement is variable within muscular dystrophies; in many of these such as Becker Muscular Dystrophy (BMD), Facio-scapulo-humeral Muscular Dystrophy (FSHD) and most of the Limb-Girdle Muscular Dystrophies (LGMD) it usually occurs over years and a follow-up is recommended every year. However, respiratory involvement may occur early in the disease and may be prominent in LGMD2I (FKRP mutation) or occur only later on in LGMD2C-F e LGMD1B [2]. In these cases, follow-up should be more frequent and similar to the more aggressive approach in DMD (Box 2). Generally, the follow-up should include measurements FVC in sitting and supine and PCF, in addition to symptom and suggestive signs of nocturnal hypoventilation detection. In case of FVC below 50% of the predicted value, or of signs and symptoms of nocturnal hypoventilation, nocturnal pulse oximetry or polygraphy are necessary. The follow-up timeline will also have to be based on the patient’s conditions: if the patient is ambulatory, one assessment per year is sufficient, while non-ambulatory patients will have to be assessed every six months [19,20].

c. Focus on DMD

Spirometry should be first performed in DMD children from 6 years of age and it should be repeated every year. Sleep studies should be considered if there is weight gain subsequent to steroid treatment or if there are symptoms of sleep-related breathing disorders (decreased attention at school, irritability, excessive daytime sleepiness) [21]. Regular vaccinations (flu and pneumococcal) should be highly recommended. Caregivers should be aware of initial signs of respiratory infections so that care can be started promptly.

Respiratory assessment: core data set.

Symptoms (fatigue, dyspnoea, morning headaches, frequent nocturnal awakenings, hypersomnolence, difficulty concentrating)

Objective signs (thoracic deformities, facial dysmorphisms, paradoxical breathing)

Spirometry with FVC, MIP, MEP, PCF

SpO2 spot measure

Nocturnal SpO2 or polygraphy

Additional test: end-tidal or transcutaneous partial pressure carbon dioxide

As disease progresses and adolescents lose the ability to walk at around a mean age of 13-14 years, respiratory monitoring (pulmonary examination, FVC, PCF, nocturnal SpO2) needs to be more frequent, and repeated every 6 months, specifically looking for symptoms of nocturnal hypoventilation. When FVC drops below 60% of the predicted value, air stacking techniques need to be introduced. Peak cough flow needs to be carefully determined when FVC drops below 50% of the predicted value or MEP is less than 60 cm H2O and if the PCF is less than 270 L/min, patient needs close monitoring. In the late non-ambulatory stages, the criteria for NIV initiation should be re-evaluated every 6 months [8].

d. Focus on myotonic dystrophies

Respiratory involvement is a typical feature of Myotonic Dystrophy type 1 (DM1), with pneumonia and arrhythmias being the main cause of death in these patients [12-21]. Although reports on respiratory involvement and how this progresses over time are scanty in patients with Myotonic Dystrophy type 2 [22], there is a general agreement that, although similar to DM1, respiratory involvement is less frequent.

Congenital Myotonic Dystrophy (CDM): respiratory insufficiency is the main cause of death in CDM and it is caused by weakness of the diaphragm and intercostals muscles as well as by the failure of cerebral respiratory control because of the severe cognitive impairment. Furthermore, the weak facial and oesophagus muscles may lead to swallowing inadequacy, and dysphagia mainly for liquids resulting in chronic lung inflammation, and/or aspiration pneumonia [23].

DMD and “DMD-like dystrophies” with respiratory involvement.

Duchenne Muscular Dystrophy (DMD)

Limb-Girdle Muscular Dystrophy 2I (LGMD2I)

Myofibrillar Myopathies (MFM)

Facioscapulohumeral Dystrophy (FSH) with:

small D4Z4 arrays (< 18 kb)

early onset

moderate/severe disease

Paediatric onset myotonic dystrophy: respiratory impairment is less frequent in this group of children and adolescents. However, weakness of the respiratory muscles may affect the ability to cough, resulting in atelectasis, chronic lung infections, chronic bronchitis and bronchiectasis. Furthermore, as in new-borns, dysphagia may be present, and children may not be aware of it, so that they may be at risk for aspiration pneumonia.

Adult onset myotonic dystrophy: weakness of the respiratory muscles affects the ability to cough, resulting in atelectasis, chronic lung infections, chronic bronchitis and bronchiectasis. Weakness of the diaphragm and possibly diaphragmatic and respiratory muscles myotonia [24] may lead to nocturnal hypoventilation. This condition is worsened by sleep apnoea, leading to disrupted sleep, excessive fatigue, and morning headaches potentially contributing to lethal cardiac arrhythmias. Excessive daytime sleepiness (EDS) is in fact one of the most frequent complaints reported in this patient population reaching a prevalence of up to 88% in some studies [25-27] and may be the presenting symptom of DM1, not infrequently, years preceding the diagnosis. Although mostly of central origin, EDS may coexist with sleep-related breathing disorders (SRBD) in some patients with DM1 [28]. Symptoms related to chronic respiratory insufficiency such as nocturnal hypoxemia and diurnal hypercapnia may be overlooked by the patients themselves probably because these gas abnormalities develop slowly, allowing brain/brainstem structures to adapt to these changes. It is not infrequent to find patients with unusually high levels of daytime hypercapnia not complaining of respiratory problems and who do not necessarily report EDS [29]. Both peripheral and central components of EDS can be approached with existing treatment strategies. NIV is recommended to treat nocturnal hypoventilation related to chronic respiratory insufficiency but compliance is limited and despite NIV, EDS may persist. On the other hand, although off-label, modafinil may be used for the central component of EDS.

Late-onset myotonic dystrophy: respiratory impairment is not typically the most frequent complaint although the data on this specific subgroup of patients is scanty. The general impression is that disease progression may be more rapid than in the adult onset, so that respiratory monitoring is recommended despite the lack of symptoms or findings on initial assessments.

Criteria for starting non-invasive ventilation (NIV)

A reduction in vital capacity (VC), total lung capacity (TLC) and functional residual capacity (FRC) determine a respiratory deficiency which has a variable course between different disorders [30,31]. Nocturnal Hypoventilation (NH) occurring especially during rapid eye movement sleep phase is the first manifestation of chronic respiratory insufficiency in neuromuscular disorders (NMD). It is unclear which definition of NH best relates to prognosis [32,33]. A correlation between the reduction of VC and progression of sleep disordered breathing has been shown in patients with NMD [34]. Daytime clinical assessments can be unreliable in early detection of respiratory failure because clinical symptoms of NH can be insidious and not always present [35]. Early recognition of NH is very important because it can progress to daytime hypercapnia (partial carbon dioxide pressure [PaCO2] > 45 mmHg in arterial blood) or clinical symptoms related to hypoventilation if it is undiagnosed and therefore untreated with NIV [36] (Box 3). Well-timed use of NIV is effective to reduce NH and its progression towards daytime hypercapnia [37]. NIV should be started in the presence of daytime hypercapnia and/or clinical symptoms as recommended in the current guidelines [38-40]. NH diagnosis is not easy in NMD in which hypoventilation is defined as pCO2 > 50 mmHg for a period longer than 25% of sleep time [41,42] and this is because it is specifically studied in the paediatric population. Transcutaneous monitoring of pCO2 levels could detect NH, even in patients that don’t show symptoms and significant nocturnal hypoxaemia [43,44] with similar results reported although the study group included a much wider population of respiratory restrictive disorders other than NMD. Finally, Ogna et al. [45] demonstrated the usefulness of tcPCO2/SpO2 as a NH diagnostic tool and suggested that a better definition of the NH threshold is needed. However, it is still not clear if nocturnal monitoring can be used as an additional tool to decide when to start NIV in clinical setting. Nocturnal polysomnography (PSG) and/or pulse oximetry with carbon dioxide monitoring were recommended in the 2004 by the American Thoracic Society as an indication to NIV for DMD (39). However, PSG has some limits, because it is not universally available, it is expensive, time consuming and not available during routine evaluations [46]. Besides, PSG attributes apneas and hypopneas only to obstructive and central events rather than to inspiratory muscle dysfunction. Assessment of symptoms related to inspiratory muscle dysfunction is often delayed in patients affected by DMD [47]. Unfortunately, night-time ventilation may be insufficient, with development of daytime hypercapnia, even when appropriate NIV adjustments are made and a vigilant clinical follow-up is done [48].

Indications for NIV initiation in DMD muscular dystrophy (from Birnkrant DJ et al, Lancet Neurol 2018).

FVC less than 50% predicted value

MIP less than 60 cm H2O

PtcCO2 or petCO2 or paCO2 >/= 45 mm Hg

Baseline SpO2 less than 95% in room air (post airway clearance)

Critical issues with NIV

Age: patient age at initiation of NIV treatment is a prognostic factor, in fact, those patients that require NIV before the age of 17 have a worse prognosis than those starting NIV at an older age. Due to improvements in respiratory care death by cardiac causes has become more common, indicating the need for active cardiology support as this approach may improve outcome.

Facial interface: sometimes, young patients do not easily accept NIV treatment because there is a poor tolerance of the interface, and this can be induced by various factors, such as excessive oral air leakage, excessive pressure of the mask on the face, claustrophobia, anxiety (because sometimes the patient may not be able to call a family member), and patient-ventilator dyssynchrony [49]. Hence, the interface plays an important role in tolerance and usefulness of NIV use. Interfaces that cover the nose alone or the nose and mouth (oronasal interface) are the most universally used; however, they can cause gastric distension, skin breakdown, conjunctivitis and claustrophobia [50]. In addition, the application of an oronasal interface can worsen social life, since it makes it difficult to eat, drink and talk. Besides, this type of mask alters the patient’s perception of himself and may have negative psychological effects [51]. Mouthpiece ventilation (MPV) via a 15-mm or 22-mm mouthpiece device is the preferable and more comfortable alternative; however, a more active participation of the patient is needed in this case. Patients requiring daytime NIV treatment (Box 4) better accepted the nasal mask treatment during the night hours, probably because the use of MPV during daytime hours made the patients feel safe, and gradually confident enough to be treated with NIV at night. The use of the nasal mask and MPV has enabled the treatment of patients who had formerly refused nasal, oral or oronasal interfaces. The possibility of using a mouthpiece as first choice interface for patients affected by DMD who need to start diurnal NIV treatment should always be kept in mind.

Daytime NIV options.

Multiple interfaces options (nasal, oro-nasal, mouthpiece)

Warning skin lesions prevention

IAPV (intermittent abdominal pressure ventilation)

Negative ventilation

NIV monitoring

Once home mechanical ventilation (HMV) is carried out, it is required a regular follow-up to assess both optimal tolerance and efficiency of the treatment is required. In addition, the measurement of both blood gases and HMV monitoring can be performed with more than one approach with an increasing level of complexity, starting from simple tools, such as oximetry, and moving to the most comprehensive sleep recording systems using in-hospital polysomnography [52]. Recently a management strategy, with a simple initial screening based on nocturnal oxygen saturation monitoring (SpO2), followed by additional exams when there are pathological findings was suggested. Non-invasive transcutaneous measure of CO2 (TcCO2) has demonstrated to have acceptable accuracy in estimating PaCO2 over numerous hours in stable patients treated with HMV [53,54] showing a higher sensitivity than SpO2 in finding residual hypoventilation in NMD patients [55,56]. Current recommendations regarding settings and monitoring of HMV are based on expert opinions [57]. The European SOMNONIV Group suggests the use of an algorithm to monitor HMV, which includes oximetry as the first screening step to detect patients who require further nocturnal exams, and advises a mean nocturnal SpO2 over 90% for at least 90% of the total recording period as a therapeutic goal. The 2010, AASM clinical practice guidelines recommend adjusting the ventilator support if hypoventilation is present for ≥ 10 minutes. Recent data showed that TcCO2 can be an accurate estimation for PaCO2 in long-term mechanically ventilated patients, with the advantage of finding episodes of transient hypoventilation, not detected by punctual arterial blood gases analyses. The use of TcCO2 opens the possibility to evaluate the ventilation’s usefulness directly and several times at home, allowing a simplification in the management of HMV. However, although capnometry devices have registered technical improvements, TcCO2 accuracy is strongly dependent on appropriate handling and knowledge of the equipment and procedures. Risk assessment is an important part of discharge planning, and risk will vary according to the use of NIV or invasive ventilation, patient’s diagnosis, the degree of ventilator dependency, functional ability and comorbidities. In a UK study a total of 188 home visits in 6 months were to analyse home problems in 1,200 patients that used predominantly NIV. About one-quarter of these problems were caused by the ventilator, while 43 were caused by technical issues (noisy equipment and recurrent alarms). No patients died or experienced side effects as a result of equipment problems in these studies. More hospitalizations were seen in the “no fault” category, in which patients or caregivers reported a ventilator malfunction. However, when a home visit was performed, a ventilator malfunction was not found; a possible explanation of this is that the patient had become unwell (usually due to an infective exacerbation) and interpreted this event as a ventilator problem [58]. These findings illustrate that patients, families and caregivers require different types of competencies, and shows that a clear problem-solving approach is needed in educating home care teams. In this area, the increasing competence to provide home telemonitoring and to observe data remotely from the ventilator has created great interest [59].

Focus on DMD: natural history studies in Duchenne muscular dystrophy (DMD), show that patients develop respiratory failure. This usually starts as nocturnal hypoventilation (NH) [60] and improves with the application of nocturnal non-invasive ventilation (NIV) [61,62]. If not treated, almost 90% of DMD patients die from pulmonary complications associated with respiratory muscle weakness between 16 and 19 years of age [63,64]. Nowadays, with the implementation of SoC, it is not infrequent to see that about half of this patient population reaches the age of 25.3-30.4 years as reported in four most favourable nocturnal NIV studies [65]. In DMD patients the vital capacity (VC) peaks are registered between 9 and 16 years of age, and then the VC decreases by 5-10% per year until ventilatory support is needed for survival [66].

Focus on DM: adaptation to NIV is limited in these patients. Symptoms related to chronic respiratory insufficiency such as nocturnal hypoxemia and diurnal hypercapnia are overlooked by the patients themselves probably because these gas abnormalities develop slowly allowing brain/brainstem structures to adapt to these changes. When NIV is prescribed as a chronic treatment option, compliance is limited mainly because of the lack of symptoms immediately related to respiratory involvement and therefore the benefits of NIV use are not perceived in the short-term nor perceived as effective by the patients. Fatigue and EDS in fact usually persist despite NIV although SRBD improves with NIV constant use. The data on the effects of withdrawal and how this affects prognosis are still scanty [67-68].

Indications for tracheostomy

Use of home non-Invasive Ventilation (NIV) in neuromuscular disease (NMD) patients with chronic respiratory failure (CRF) may be expected to extend survival by many years, improve physiologic function and quality of life as well as decrease the frequency of episodes requiring acute care facilities [64]. Based on these considerations and the fact that safety, comfort, satisfactory speech and swallowing have been reported by long-term users, NIV should be regarded as the therapy of choice in supporting breathing in DMD [69]. Nevertheless, a significant proportion of DMD individuals are currently prescribed tracheostomy ventilation (TV) for home ventilatory care. Indeed, recent data published by one of the 14 reference centres for NMD in France, showed that 31 out of 150 DMD patients who had undergone long-term mechanical ventilation (LTMV) between 1997 and 2014 had initiated ventilatory assistance via a tracheostomy, although mechanical ventilation had increasingly started using a non-invasive interface over the course of the study period [70]. In most cases, the decision to perform a tracheostomy is taken when NIV becomes ineffective: according to recent data collected by MD STARnet, the largest population-based surveillance system of individuals with DMD and Becker muscular dystrophy (BMD) in the United States, approximately 90% of patients had received tracheostomy following NIV treatment failure [71].

When to perform a tracheostomy?

Placement of a tracheostomy may be considered both in the event of a life-threatening acute illness that has required invasive management and when a slowly progressive ventilatory failure is present. Indeed, although the non-invasive approach, based on the combination of NIV and assisted coughing techniques, in particular Mechanical Insufflation–Exsufflation (MI-E), should be preferred as a first-line intervention for patients with DMD during an episode of Acute Respiratory Failure (ARF), moving [72] on to invasive ventilation with intubation becomes unavoidable in case of NIV failure, inability to clear secretions with cough assist and suctioning or the loss of ability to protect the airway with high risk of aspiration. Unfortunately [73], once intubated, a substantial proportion of NMD patients may encounter particular difficulties while being liberated from the endotracheal tube after recovery from the acute illness, due to weakness of the inspiratory muscles, inadequate cough and inability to handle oropharyngeal secretions, thereby having to switch to a tracheostomy [74]. Of notice, a large uncontrolled study unexpectedly reported that the standardized use of NIV and cough assistance may lead to an effective extubation of the great majority of “unweanable” NMD patients who could not pass a spontaneous breathing trial [75].

In DMD patients with chronic, progressive ventilatory failure, indications for performing a tracheostomy have not been clearly defined [76]. According to the consensus conference of the American College of Chest Physicians, and more recently the American Thoracic Society consensus for DMD respiratory care [39], severely impaired swallowing, leading to chronic aspiration and repeated pneumonia, and/or ineffective clearing of tracheobronchial secretions, despite the use of non-invasive manual or mechanical expiratory aids, have been considered to be indications for TV. In current practice, no level of pulmonary function or blood-gas abnormality absolutely mandates tracheostomy over NIV. However, a Vital Capacity (VC) value below 20% predicted, a PaCO2 level above or equal to 45 mmHg during assisted breathing, a need for increased ventilation time, and a severe clinical status at initiation of NIV, suggest an overall risk of NIV failure and the forthcoming need for a tracheostomy [77]. Morphologic characteristics of the patient, as difficult intubation prediction, and environmental circumstances determining the ease or difficulty in using emergency service are to be taken into account as well.

In line with the recent German national guideline for treating CRF [78] indications for tracheostomy in NMD patients have been summarized in Box 5 and Box 6.

How and where to perform tracheostomy?

Performance of a tracheostomy as an elective procedure by skilled surgeons and follow-up care in specialized centres may reduce the risk of early and/or late postoperative complications [79].

In literature, there are no specific indications about tracheostomy implementation, percutaneous or surgical [80], but it has been agreed by the participants that, in case of long- term tracheostomy, the surgical technique is preferred. Such indications reflect the need for an easier and safer periodic tube change, a lower risk in case of stable surgical stoma, reduced accidental decannulations, always fearsome when dealing with totally ventilator dependent patients [81]. Risk factors that can complicate the tracheostomy change include obesity, a short neck, anatomical abnormalities, excessive granulation tissue, lack of patient cooperation. In case of tracheostomy recently performed (in the previous 2 weeks) or in case of an anticipated difficult tracheal tube exchange, we suggest using the “railroad” technique with a guiding obturator [82].

Impact on patients and family

Once long-term TV is initiated, DMD patients require special considerations for care. Outcome and patient comfort are improved with the application of a well-conceived management plan including education for patients, families, and health-care providers, and by an active role by home-care agencies in providing care to these patients [83].

Indications for tracheostomy in neuromuscular disease patients (from Windisch W et al. Respiration 2018;96:171-203, mod.) [78].

Inability to fit an appropriate ventilation interface

NIV intolerance

NIV inefficiency

Severe bulbar symptoms with recurrent aspiration

Inefficiency of non-invasive secretion management

Failure to switch to NIV after intubation and invasive ventilation

Recommendations for patients who are expected to be on long-term IV (from Windisch W et al. Respiration 2018;96:171-203, mod.) [78].

Tracheostomy for long term ventilation should be performed surgically and not percutaneously

Patients on NIV ≥ 16 hours a day need to be equipped with 2 ventilators, one acting as a back-up, and need to have an external battery

Patients need to be equipped with an oximetry machine

Patients need to be provided with an extra tracheostomy tube of a smaller diameter than the one in place in case the tube gets removed accidentally and needs to be promptly replaced at home

In order to use a speaking valve, patients’ cuff must be deflated

The ventilator needs to be provided with active an humidifier so that the air inspired is sufficiently humified and warm

2 suction machines are required

Being unable to speak is a major cause of frustration for patients with a tracheostomy tube and their families: a tracheostomy, however, presents opportunities to promote articulated speech. Airflow through the upper airway and vocal cords is necessary for voice production: for this reason, partial cuff deflation may allow the patient to speak in a whisper during the inspiratory phase of the respiratory cycle. Adding a small amount of positive end-expiratory pressure produces a continued air leak and permits audible speech throughout the breathing cycle [84]. Moreover, subjects with minimal ventilator requirements can be ventilated with cuffless tubes that allow a constant air leak and the ability to speak. Finally, the use of a one-way valve, such as a Passy-Muir valve, allows airflow through the tracheostomy tube during inspiration but does not permit air to exit the tracheostomy tube during exhalation. When the valve is employed with a cuffless or fenestrated tracheostomy tube, expiratory airflow is directed through the vocal cords and normal speech is facilitated [85].

A comparison of morbidity and causes of death in a number of DMD patients receiving full-time mechanical ventilation either by tracheostomy or by NIV, showed that the risk of complications was higher in tracheostomized compared with NIV patients, in particular mucus hypersecretion and tracheal injuries [86]. Furthermore, data on mortality showed that the risk of death at 12 years does not significantly differ between DMD subjects undergoing long-term NIV or TV [87].

In conclusion, the decision to perform a tracheostomy in DMD ventilator-dependent individuals is complex and involves medical, ethical and financial considerations. Patients giving their consent to its application may live at home despite NIV failure.

Secretion management

Respiratory insufficiency and pneumonia are primary causes of mortality and comorbidity in many NMDs [2]. Airway clearance techniques (ACT) are an essential component to the care of people with NMDs. During acute respiratory tract infections, patients with NMDs develop dyspnoea, hypercapnia and a reduction in both respiratory muscle strength and lung function [88].

What is important to control regularly?

Among, the various measurable parameters, the most useful, when referring to cough efficacy, are:

Vital Capacity (VC);

Maximal Insufflation Capacity (MIC);

Peak Cough Flow (PCF).

VC and MIC can be measured by a simple portable spirometer or flow meter. MIC, the maximum capacity of keeping air in the lungs, starting from vital capacity, through air-stacking manoeuvres, represents the best rib cage elasticity index: it should be measured when VC is below 2000 ml or at 50% of predicted in adults [89]. In the evaluation of cough efficacy, PCF is the most reliable and simple to use assessment at the patient’s bedside [90,91], reference values are available for children [92] and adults: cut-off values for cough efficacy in normal adults range from 360 to 840 L/min [93]. The PCF can be easily measured with a hand-held flow meter or a pneumotachograph/spirometer [94] using an oro-nasal mask or a mouthpiece [95]. When the values are higher than 270-300 L/min, they are believed to be safe because it is expected that a PCF > 160 can be maintained during episodes of exacerbation [96]. In clinical practice, an efficient cough requests a PCF higher than 160-200 L/min [97].

What to do when PCF < 270 L/min or VC < 50% or < 2000 ml?

It is important to regularly measure PFC and VC as, even in case of significative muscular weakness, the patient might not experience symptoms in everyday life. If PCF values are stably below 270 Litres/minute or VC < 50% of predicted or < 2000 ml in an adult patient, it is necessary to introduce cough assistance techniques, either manual or mechanical.

a. Manually assisted coughing

Manual cough assistance techniques can assist the inspiratory or expiratory phase, or both.

Assisted inspiration

In order to produce an efficient cough, deep inspiration preceding the expiratory phase is essential. The quantity of inhaled air can be increased by using an AMBU bag in the air-stacking manoeuvre, or by the use of mechanical ventilator in volumetric mode, with the inhalation of one or more consecutive breaths, without breathing out, in order to obtain a full deep breath. Some patients are able to learn glossopharyngeal breathing (GPB), that allows improved air stacking in the absence of any respiratory device.

Assisted expiration

Manual assistance manoeuvre in the cough expiratory phase consists in chest and abdomen compressions by the caregiver to improve the expiratory flow and promote secretions removal.

b. Mechanical in-exsufflation

Mechanical in-exsufflation (MI-E) is a very popular cough augmentation technique [98]. MI-E devices produce inspiratory and expiratory assistance. MI-E is well tolerated [30] and may be delivered by non-invasive or invasive [99] interfaces. MI-E associated with manual assisted coughing, oximetry feedback and home use of non-invasive ventilation was shown to effectively decrease hospitalizations and respiratory complications and mortality in a program for patients with amyotrophic lateral sclerosis [100].

How to manage deep secretions?

Peripheral ACT incorporates the techniques that aim to improve ventilation and enhance mucus transport from the bronchi to the upper airways. Different techniques have the potential to loosen secretions and transport them from the peripheral to the proximal airways: these include High Frequency Chest Wall Oscillations (HFCWO), Intrapulmonary Percussive Ventilation (IPV), and Chest Wall Strapping (CWS) [101]. Peripheral ACT does not require the patient’s co-operation. The use of these techniques is possible in infants, children and adults, even in the presence of a tracheostomy and/or bulbar failure or intellectual impairment. Carers must know that peripheral secretions cannot be mobilized in patients who have retained proximal airways secretions. Rather, it is recommended to use peripheral ACT after more central airways are cleaned of secretions by means of proximal ACT. In other words, sessions of airway clearance should first empty the proximal airways and then, if the patient is not too tired, mobilize secretions from the peripheral airways. If patients are exhausted, it is not recommended to approach the patient with peripheral ACT because these will not be tolerated and cough will be ineffective. This could put the patient at risk of having a respiratory arrest because of the excess of secretions without being able to get rid of them using a cough-machine. Recommendations to manage secretions are summarized in Box 7.

Management of acute respiratory failure

ARF most often occurs during otherwise benign upper respiratory tract infections favouring mucous encumbrance, and further weakening of respiratory muscles [88] or in cases of pneumonia, aspiration or atelectasis [73]. Other causes of ARF in these patients are pneumothorax, fat embolism and abuse of sedative drugs [30]. Several muscular dystrophies are associated with dilated cardiomyopathy [102,103], which may cause pulmonary edema and favour ARF [39].

A proactive clinical approach should be taken to prevent the onset of ARF and allow carers to recognize signs and symptoms potentially leading to ARF early, such as increased respiratory rate, tachycardia, tidal volume reduction in ventilated patients [9,64,104].

Admission to the hospital for ARF can be very disruptive for these patients [105], who could be successfully managed at home by experienced and well-trained family members and/or healthcare professionals [106]. Bach and colleagues [96] described a protocol for managing these patients at home in case of respiratory tract infections, reporting a dramatic reduction in the need for hospitalization and a prolongation of life expectancy. More recently, Vianello et al. showed that active treatment provided by healthcare professionals is an effective alternative to hospital admission for selected NMD patients with respiratory infections [107]. In particular, during respiratory infection, early use of antibiotics is mandatory if pulse oximetry is below 95% on room air [30]. Moreover, according to Bach’s protocol [96], the patients should receive 24-h NIV during the exacerbation. Pulse oximetry should be monitored continuously and when oxygen saturation on room air falls below 95%, secretion removal should be aggressively induced using cough assistance until oxygen saturation returns to the 95% range. Oxygen should not be used to correct hypoxaemia at home, because it can worsen hypercapnia and it does not allow the recognition of a severe hypercapnia with the pulse oximetry. Finally, family members should be trained to use strict criteria leading to urgent hospital admission, and the home treatment protocol should be tailored according to local resources.

Secretion management: recommendations.

PCF and VC assessment are suggested at every follow-up visit

A spirometer or a hand-held flow meter can be used to measure PCF keeping the same type of interface, such as oro-nasal mask or mouthpiece, in the following evaluations

The use of MI-E is safe and effective through both invasive and non-invasive interface, in paediatric and adult patient

Ending the MI-E session during the inspiratory phase is recommended to avoid phenomena of atelectasis, especially in frail patients

To avoid secretion encumbrances in patients with ineffective cough, sessions of secretions removal from central airways must be performed before and after peripheral ACTs

If home respiratory management fails, patients must be hospitalized [73]. Few prospective studies on the management of NMD with ARF [109] and some retrospective studies [64,109-112] reported the successful use of a non-invasive approach (i.e., NIV combined with assisted coughing) to improve gas exchange abnormalities and avoiding intubation. However, patient selection remains important for the success of this strategy. In particular, severe bulbar dysfunction increases the patient risk for aspiration, and hampers the elimination of airway secretions impeding successful use of non-invasive approach [108]. Close monitoring of these patients is mandatory, and NIV should never delay endotracheal intubation for most severe cases [73]. Monitoring must be tailored and personalized according to the clinical and respiratory severity of each case. In particular, PaCO2 measurement (i.e., capillary CO2 in mild disease and indwelling arterial line in most severe cases) must be included if supplemental oxygen is used to correct hypoxemia [113]. It follows that these patients should be admitted in a unit where medical and nursing staff is adequately equipped to apply close monitoring and aggressive non-invasive respiratory assistance. Also in this setting the continuous presence of well-trained care-givers is important for the success of the treatment [73] Caregivers may provide continuous care, including repositioning of mask and administration of cough machine; otherwise, the presence of a skilled nurse is needed, with a nurse-patient ratio of 1:1 [104].

If a non-invasive approach fails or is contraindicated, patients can be intubated as a short-term measure. In this case, assessment for a difficult intubation due to reduced mouth opening, macroglossia or limited mobility of the cervical spine is very important. If any of these conditions are present, intubation should be performed taking into account the guidelines for difficult airway management avoiding emergency intubation [114].

After recovery from the acute illness, patients with muscular dystrophies should be promptly extubated. Unfortunately, because of weakness of the inspiratory muscles, inadequate cough, and inability to handle oropharyngeal secretions, a substantial proportion of these patients fail the weaning process [115]. Preventive application of NIV combined with assisted coughing after extubation provides a clinically important advantage to these patients by avoiding the need for reintubation or tracheostomy and shortening their stay in the ICU [116]. Moreover, Bach and al. suggest using cough assistance devices before extubation to clear the airways. Once SpO2 is maintained > 95% on ambient air, patient should be extubated to full NIV support and aggressive cough machine to maintain or return to the SpO2 > 95%. The indication for a tracheostomy can be evaluated, but it should not be considered in the acute phase. In particular Bach and al. suggest to consider tracheostomy only in case of multiple failures with the application of the discontinuation protocol [75]. Recommendations suggested for patients with muscular dystrophies in case of emergency management are summarized in Box 8.

Care choices and advanced directives

Although NMDs are uniformly fatal, each has a different life expectancy and disease trajectory that potentially influences health care decisions and raises unique ethical concerns. The burden of NMDs is high with consequences requiring repeated and extended hospitalizations, clinical management and frequent interactions with clinicians of many different specialties.

Some of the ethical challenges raised by NMDs include the choice and effectiveness of life-sustaining therapies and advance care planning: these issues involve informed consent and end-of-life care [117].

Palliative care (PC) is an “active and global care of patients suffering from diseases that cannot be cured, in order to control pain, dyspnoea and including psychological, social and spiritual aspects” [118]. The uncertainties that arise in caring for NMDs, coupled with the increasing availability of therapies and technologies, create complex ethical quandaries for families, caregivers, society, school and clinicians. Such quandaries are exacerbated by the certainty from the time of diagnosis that these diseases are life limiting [117]. The most frequent and stressful ethical challenges for NMDs occur in regards to ventilator support, ventilatory support (benefit vs harm), families wishes to receive long-term tracheostomy ventilation [119-121], palliative management, differences in opinion between family members and differences in physician opinions. For NMDs there are triggers for referral to palliative care services [122].

Emergency management: recommendations.

Clinicians must know that the development of respiratory tract infections in patients with muscular dystrophies, is a life-threatening event favouring the appearance of mucous encumbrance and further weakening of respiratory muscles that leads to ARF.

A proactive clinical approach should be taken to recognize pulmonary problems prior to the onset of respiratory compromise. Patients who have a FVC <50% of predicted value can be trained to use a protocol that provides indications for the use of NIV, cough assistance and pulse oximetry in case of respiratory infections.

NIV combined with mechanically assisted coughing has been established as standard practice in patients with muscular dystrophies affected by ARF either in the outpatient or in the inpatient (hospital). In particular, techniques to aid secretion removal must be applied aggressively if bronchial encumbrance is present.

During respiratory exacerbations they can be successfully managed at home if family members are well-trained to use NIV, cough assistance and pulse oximetry. Oxygen alone should not be used to correct hypoxemia. Early use of antibiotics is mandatory. Family members should be trained to use a protocol that defines also when patients need urgent hospitalization. This protocol should be tailored according to local resources.

If home respiratory management fails, patients with muscular dystrophies must be hospitalized and they should be placed in a unit where medical and nursing staff is adequately equipped for the aggressive management of these children and close monitoring. Monitoring must be tailored and personalized according to the clinical severity of each case.

The continuous presence of well-trained parents or other care-givers is important for the treatment success also in the critical care setting.

The use of NIV should not delay endotracheal intubation for most severe cases, avoiding emergency intubation.

After recovery from the acute illness, patients with muscular dystrophies should be promptly extubated and started immediately on NIV and cough assistance. Tracheostomy should not be considered in the acute phase and should be considered only in case of multiple failures of weaning protocol.

In summary, factors influencing patient/family decisions for ethical concerns are local tradition, level of home assistance, stress, patient’s age, where they lived, confusion about disease severity, internet information bias, variability in management across specialties and countries, cases reported in the media, paucity of quality-of-life data, lack of anticipatory care planning (ACP) resulting in critical decision making. NMDs patients frequently die in ICU and acute settings, have a low level of awareness about their disease prognosis [123]. Italian respiratory units have, only in a minority of cases, a clear ACP and palliative/end of life plan [124]. ACP is the process of communication between individuals and professional caregivers that includes, but is not limited to, options for end-of-life care and the completion of advanced directives. Typically, for NMDs and during an emergency, decisions may be made by clinicians who are unfamiliar with the child, and there is little time for confrontation [119]. Like other types of preventive medicine, ACP are underutilized even though they are cheap, low-tech, and potentially highly effective [125]. ACP facilitate the application of the proportionality care principle, pain/dyspnoea/anxiety treatment, informed consent, doctor/patient relationship, psychological assistance and trustee administrator presence. On the contrary, ACP could compromise the relationship between doctor and patient due to the mandatory respect of a pure contract; the possibility to refuse incongruous requests in the presence of new undefined therapies, the lack of clear patient informed competence, the risk of conflict between trustee administrator and family and the debate over artificial nutrition and hydration as care treatments, may remain unresolved problems. Recommendations for advanced directives are summarized in Box 9.

Conclusions

There is increasing evidence of a link between respiratory and mental health [126]. In fact, literature suggests that in patients with chronic respiratory diseases, the evaluation of breathlessness perception, psychological disturbances and the recording of any stressful event should be considered as relevant as the physical and functional assessment of respiration [127].

In severe neurological conditions, ventilator users can present mainly two types of needs: respiratory related needs, including mode of ventilation prescription and selection, maintenance of lung recruitment and good airway clearance; non-respiratory related needs, including substantial nursing care, adequate nutrition, accessible communication and psychological support. It is relevant to pay attention to all of these needs with the aim to maintain patients’ quality of life (Qol) [128].

A UILDM - Telethon study provides evidence in favour of an integrated care model for muscular dystrophies that is suitable for: pharmacological treatment, rehabilitative interventions [129], psychological treatments, welfare and financial support [130]. Medical care of a patient with DMD and his family is not complete without support for their psychosocial wellbeing [131]. The families’ lives change significantly with the decision to place their child with NMD on HMV because of the experience of a recurrent sense of loss and uncertainty. It would be suitable to improve support by health care professionals, their extended family, and their community, to enable parents to fulfil their vital role [132].

Care choices and advanced directives.

1. A frank, early and individualized conversation is mandatory:

Listen and talk to your patients

Consider and imagine their preferences and future

2. Timing of conversation with patients/family:

ICU admission

Hospitalization for respiratory reasons

Continuous NIV for more than 16 hours/day

Persisting hypoxemia during NIV use

Severe comorbidities (congestive cardiac failure, gastro-intestinal pseudo-obstruction)

Severe malnutrition

Bulbar symptoms

Recurrent infection and severe malnutrition during tracheostomy ventilation

Cognitive deficit

Poor family network

3. Push for anticipatory care planning (ACP):

Decisions should be made in advance and not during an acute situation

Decisions must be individualized and based on the most objective criteria possible

Extend survival improving quality of life and facilitating the patient spending as much time as possible at home

ACP can be extended to all life support measures including the DNR and withdraw from MV

4. Doctor/team responsibility

The doctor has the legal and ethical responsibility to propose all options treatment including MV

The doctor should avoid personal perception

A multidisciplinary approach is recommended

An ethical committee involvement is welcomed also for moral distress and conflicts of conscience

Team training is needed

5. Taking care of end of life time

Check patient’s physical and psychosocial symptoms

Do not unduly prolong life and suffering

Patients who choose not to resort to MV should receive adequate end of life care

Facilitate the presence of family, friendly people and religious comfort

Consider hospice competencies and palliative care consultation services for your patients (“Home hospice” care could be preferred)

Interestingly, parents of paediatric neuromuscular patients requiring HMV did not refer significantly higher parental stress compared to parents of non-ventilated children, despite their children having a lower health-related Qol; this data suggests that parents living with a continuous care demand could undergo a progressive adjustment process allowing them to consider respiratory care as a part of “normal” life, thus without the perception of this being an additional source of stress [133].

A number of ethical challenges, or dilemmas, can arise alongside treatment progression: the decision-making process regarding whom HMV should be offered to, respect for patient and family wishes, Qol, dignity and equal access to dedicated assistance. Moreover there is uncertainty regarding the impacts of HMV on the patient, the family, the healthcare services and the allocation of resources. A better and broader understanding of these issues is crucial in order to improve the quality of care for both patient and family and to assist HMV professionals to improve the decision-making process and to keep the patient and his or her family highly involved [121].

Improvement and standardization of care pathways, with a better management of comorbidities related to neuromuscular diseases, has led to an increase in life expectancy and an increased number of patients reaching adulthood. Adolescence and adulthood are age groups in which new and challenging problems may develop. Care of children with chronic disorders is often complex, involving a high level of ongoing interaction between caregivers and the multidisciplinary health care team.

The transition from childhood to adulthood has therefore become an emerging problem that involves medical, psychological, social and economic aspects centred on the family. An unmanaged, non-standardized transition increases the risk of adverse outcomes. During this critical period, these patients are at increased risk for interrupted health care and related negative health consequences: They must cohabit with their progressive disability: decreased mobility, decreased independence for hygiene, increased needs of technological support. increased survival rate but at the same time increased morbidity. In general, the diagnosis is made in paediatric age and the co-morbidities develop starting from adolescence.

It is necessary to develop a standardized multidisciplinary transitional program focused on the needs of the patient around which the various professionals must gravitate. Health care providers and educators are among the best facilitators for discussions around health, education, sexuality, employment, social development and adult living. Therefore, the role of the care coordinator becomes fundamental in obtaining the goal of transition which is to optimize the quality of life and future potentiality of young patients with special health care needs.

Providing guidance on transfer of medical information and developing an individualized care plan for these children becomes essential to draw up a transition policy with planning tools (transition readiness assessment, portable medical summary and transition action plan).

Preparing young adults for the change in health care setting is crucial for a successful transition to adult care: there is no right time, but a timely and organized transfer must be discussed and planned before transitioning to adult health care providers.

The critical aspect of implementing the guidelines/recommendations, present in literature for each neuromuscular pathology, is usually determined by the difficulty in disseminating the scientific contents throughout the country, particularly at the local level of centres working with patients affected by neuromuscular diseases. This assumption was confirmed by the results of the survey, taken by all of the workshop participating specialist centres, from which it appears that not all guidelines on respiratory management of patients affected by DMD are applied in a homogeneous way by these centres.

At the end of the meeting, a flow-chart regarding rapid evaluation of dystrophic paediatric and adult patients, that can facilitate the respiratory classification of the patients, was developed (Fig. 4).

Figure 4.

Flow-chart for rapid evaluation of respiratory function in muscular dystrophy.

The aim of this document is to facilitate the dissemination and application of essential respiratory care considerations for patients affected by muscular dystrophy, by hospitals and local clinical centres who do not routinely work with, but that could be involved in acute and chronic care of these patients. We are aware of the fact that the management of the respiratory involvement of paediatric and adult patients affected by muscular dystrophy should be as individualized as possible; nonetheless, we believe that patient educational training, and most important of the caregiver, has a significant impact in the course of treatment. For this reason, this paper has some, patient and caregiver cards attached that, describe the management of the most important respiratory issues that occur throughout the life of patients affected by muscular dystrophy such as:

air stacking exercises;

mechanical cough assistance;

non-invasive ventilation;

ventilation through tracheostomy critical aspects;

mouthpiece ventilation.

We hope the result of this work can encourage and facilitate the respiratory care for all the centres that will have to deal, even occasionally, with the respiratory management of patients affected by muscular dystrophy and their families.

Survey results of participating centres for DMD ambulatory stage patients.

Survey results of participating centres for DMD early non-ambulatory stage patients.

Survey results of participating centres for DMD late non-ambulatory stage patients.