Respiratory management of adult patients with progressive neuromuscular disease: Non-invasive ventilation and the role of the Intensivist

ARTICLE IN PRESS Current Anaesthesia & Critical Care (2007) 18, 237–251

www.elsevier.com/locate/cacc

FOCUS ON: NEUROLOGY IN ICU

Respiratory management of adult patients with progressive neuromuscular disease: Non-invasive ventilation and the role of the Intensivist Peter Robinsona,, James Douglasa, Carole Footb a

Sleep Disorders Centre, Prince Charles Hospital, Rode Road, Chermside, Queensland 4032, Australia Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia

b

KEYWORDS Neuromuscular disease; Neuromuscular disorder; Ventilation; Intensive care

Summary Non-invasive positive pressure ventilation (NIV) is now widely used for a variety of chronic neuromuscular diseases, and available evidence demonstrates improved quality and quantity of life. Clinicians should be aware of the natural history of each neuromuscular disorder in order to make informed decisions about life-prolonging therapies in the intensive care setting. Attention to co-morbidities and reversible causes of exacerbations of respiratory failure are important given that these are often treatable. Nutritional factors play an important role in patients receiving NIV. End of life planning should be discussed with all patients requiring noninvasive ventilation. & 2007 Published by Elsevier Ltd.

Introduction Respiratory care of patients with chronic progressive neuromuscular disease has evolved considerably in the last 20 years. Non-invasive ventilation (NIV) has improved both quality of life and length of life of patients with some of these diseases. Considerable advances in both mask interfaces and ventilators since the 1990s have translated to an increased utilisation of this therapy, and conse-

Corresponding author. Tel.: +61 731394000; fax: +61 731396053. E-mail address: [email protected] (P. Robinson).

0953-7112/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.cacc.2007.09.004

quently there are an increasing number of patients who rely on this therapy to maintain their quality of life. As a result of increasingly interventional treatment and increased expectations from patients and their families, it is likely that Intensivists will be called upon to provide support from time to time. The most common chronic neuromuscular diseases that are encountered are Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM) and motor neurone disease (MND). Each has its own co-morbidities, natural history and prognosis. Other causes of neuromuscular disease causing respiratory failure are beyond the scope of this review; however, many of the general principles discussed are applicable to such patients.

ARTICLE IN PRESS 238 Patients with chronic neuromuscular disease have complex care needs and require a great deal of time and support to assist them and their families with decision-making throughout the progression of their disease. Acute and chronic management of these patients requires a multidisciplinary approach with medical, nursing, allied health and social work teams all integral to meeting the care needs of patients and their families. In this review, we discuss the natural history of these common neuromuscular disorders and focus on the respiratory management of complications, giving particular consideration to the use of NIV. The reader is also directed to current available evidence-based and consensus guidelines for managing the respiratory care of these diseases.1–5

Natural history and prognosis An awareness of the natural history of a disease is important when making decisions about lifeprolonging interventions in the intensive care unit. Considerable changes in care, including multidisciplinary clinics and increased use of noninvasive ventilation have altered the outlook for many patients with neuromuscular diseases.

Duchenne muscular dystrophy DMD is the most common neuromuscular disease of childhood, occurring in 1 in every 3500 male births.6 Treatment is largely supportive and mortality occurs predominantly due to respiratory or cardiac involvement. In general, DMD progresses in a predictable fashion, with loss of independent mobility between 9 and 11 years. Scoliosis of the chest wall occurs during the adolescent growth spurt between ages 11 and 16, with 50% of one cohort acquiring it between ages 12 and 15 years.7 Mean age at death without non-invasive ventilation is 19 years.8,9 A small case series followed ventilated and non-ventilated DMD patients, and found that the survival of those not ventilated who had already developed daytime hypercapnia was 9–10 months.10 The average lifespan for DMD patients has slowly improved since the 1960s, with the mean age at death of a 1960s cohort being 14.4 years, compared to a cohort ventilated non-invasively since 1990 having a mean age at death of 25.3 years.9 In this cohort, presence of cardiomyopathy decreased mean lifespan by 2.1 years; however, this also was prior to the introduction of improved medical therapy for cardiomyopathy. The improvement in

P. Robinson et al. mortality since 1990 has been seen in several centres, with all demonstrating an increased proportion of patients surviving to 25 years and beyond, associated with improved multi-disciplinary care and increased utilisation of non-invasive ventilation since that time.9,11 Respiratory failure is the most common cause of death, causing death in 82% of muscular dystrophy cases in a UK series based on death certificate data.8

Myotonic dystrophy DM is a heterogeneous group of disorders with shared phenotypic features and genetic abnormalities detected at one of two loci, 19q13.3 or 3q21.3.12 Estimated prevalence ranges from 1 to 14.3 per 100 000 worldwide, and higher geographical clusters occur, such as in the province of Quebec in Canada.6,13 Classical myotonic dystrophy (DM1) is characterised by a trinucleotide repeat at the 19q locus. The disease is autosomal dominant and displays anticipation with each generation. Clinical severity increases with the length of trinucleotide repeat. Age of onset varies from a congenital form to adult-onset disease and inversely correlates with number of trinucleotide repeats. The characteristic phenotype varies with age of onset; however, typically involves distal limb and facial muscle wasting, weakness and myotonia, intellectual impairment, cataracts, insulin resistance and cardiac conduction abnormalities. Type 2 myotonic dystrophy (DM2) is more recently described but appears to be a less severe disease with minimal evidence for CNS or respiratory involvement and no congenital cases.14 Type 1 myotonic dystrophy (DM1) is a slowly progressive disease with variable age at onset. It is the commonest adult-onset muscular dystrophy. A previous cohort study of 367 myotonic dystrophy patients followed over 10 years from 1984 showed that respiratory disease was the major cause of mortality (43%) followed by cardiac disease (20%), neoplasia (8%) and sudden death (8%), possibly as a result of cardiac arrhythmia.15 Overall, mortality in DM1 patients was 7.3 times higher than an agematched reference population. Mean age at death in this cohort was 53.2 years (range 24–81) with the wide-range reflecting the variability of age of onset and disease phenotype. Proximal weakness and wheel-chair dependence were associated with reduced survival in this cohort. A Dutch cohort of 180 myotonic dystrophy patients of adult-onset had a median survival of 60 years for males and 59 years for females.16 The same cohort had pneumonia and

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease cardiac causes as the leading causes of death, each accounting for approximately 30% of deaths.

Motor neurone disease MND is an idiopathic degenerative disease of upper and lower motor neurons. Both sporadic and familial forms are recognised. Age of onset is widely variable, with a median age at onset of 62 years in the sporadic form. Difficulties in ascertaining a definite diagnosis and heterogeneity of disease progression make individual prognostication difficult; however, certain factors are known to be associated with a poorer prognosis. These include older age at onset, bulbar-onset disease, BMIo18.5 and rapid progression early in the course of the disease.17,18 Average length of survival is variable, with reported rates of survival 32–39 months from onset of symptoms, and 19–30 months from diagnosis. Several interventions have been shown to improve length of life. These include Riluzole, a glutamate antagonist, which offers a 2–3 month survival advantage, and non-invasive ventilation (see below).19–21 Respiratory failure and pneumonia are the most frequent cause of death. One retrospective review of MND patients with respiratory symptoms at the onset of their disease found a similar survival as those with bulbar-onset disease, with a mean survival of 27 months.22

Respiratory evaluation Predicting the optimal time of when to commence non-invasive ventilation can be difficult. Published series often contain heterogenous populations of patients with different neuromuscular diseases. In general terms, loss of respiratory muscle function occurs gradually and remains asymptomatic until a significant decline has occurred. The level of lung function at which symptoms occur is somewhat variable between individuals. Respiratory muscle weakness leads to impaired coughing, reduced ventilation, atelectasis and eventually pneumonia and hypercapnic respiratory failure. Additionally, nocturnal hypoventilation via a combination of respiratory muscle weakness and reduction in chemoreceptor sensitivity can produce sleep related breathing symptoms such as, sleep disruption, early morning headaches and daytime sleepiness. Finally, diaphragmatic dysfunction manifesting as orthopnoea can be prominent especially in MND. An important part of the management of patients with neuromuscular disease is monitoring for the

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development of respiratory muscle involvement, sleep-disordered breathing and hypercapnic respiratory failure. Various studies have looked at the ability of static lung function tests to predict the onset of respiratory failure and sleep-disordered breathing in these diseases. General methods for assessment of respiratory muscle weakness include spirometry, and respiratory muscle pressure testing. Spirometry performed in lying and sitting positions can give a reproducible indication of diaphragmatic weakness, with a decline of 420% in VC between sitting and lying positions a good indicator of diaphragm weakness. Measurement of respiratory muscle pressures can yield variable results and reproducibility is more difficult to achieve; however, sniff nasal pressure testing may be a more reliable form of testing inspiratory muscle pressure. Arterial blood gases are important in documenting daytime hypercapnia. Additionally, elevated bicarbonate in the presence of normocapnia raises the possibility of nocturnal hypoventilation. Sleep studies with oximetry and transcutaneous CO2 monitoring are useful to document nocturnal hypoventilation. The three neurological conditions discussed in this paper all have differing patterns of respiratory muscle involvement and require a tailored approach.

DMD A large longitudinal cohort study of 162 DMD patients followed over 10 years demonstrated the typical age-related changes in respiratory physiology which occur in this group.7 Overall, 34% of these subjects had respiratory complications such as pneumonia or acute respiratory failure, with increasing lifetime prevalence with age, from 7% at ages 3–8, to 68% in those aged over 21 years. Of those who underwent serial lung function testing, forced vital capacity (FVC) decline was most prominent during the 10–20 year age group, declining at an average rate of 8.5% per year, and subsequently 6.2% per year after age 20. The rate of respiratory complications was also highly correlated with reduced per cent predicted vital capacity (VC), but not with the presence of spinal deformity beyond the effect seen with ageing. Maximal static airway pressures (MIPs and MEPs) showed a decline with ageing, and this decline appeared earlier than that of FVC. Debate continues as to the best non-invasive test to monitor respiratory status in DMD patients. Studies looking at lung function predictors of hypercapnia and sleep-disordered breathing in

ARTICLE IN PRESS 240 DMD have demonstrated the following:

  



The age when VC fell below 1 L was a strong marker of subsequent mortality (5-year survival ¼ 8%) in a longitudinal cohort of DMD patients.23 An FEV1o40% was a sensitive (91%) but not specific (50%) indicator of sleep hypoventilation in those not receiving NIV.24 PaCO2 of 445 mmHg was an equally sensitive (91%) but more specific (75%) indicator of sleep hypoventilation, while a base excess of 44 mmol/L was highly specific (100%) but less sensitive (55%) for sleep hypoventilation.24 Hypoventilation occurred in all sleep stages, and DMD patients with diaphragmatic dysfunction were especially vulnerable to oxygen desaturation during REM sleep.25

The spectrum of sleep-disordered breathing encountered in patients with DMD extends beyond hypoventilation. Most studies have demonstrated central sleep apnoea; however, obstructive apnoeas can occur in this population in the setting of snoring or macroglossia.26,27 Consensus guidelines suggest DMD patients confined to a wheelchair, those with a fall in VC to o80% predicted, or those 412 years of age should have twice-yearly review with a respiratory physician. Our approach is to measure spirometry routinely at each visit and perform arterial blood gases when FEV1 is o40% predicted or there are symptoms of sleep-disordered breathing. Sleep studies are reserved for those with symptoms of sleep-disordered breathing or abnormalities on arterial blood gases as described above.

Myotonic dystrophy (DM) Studies of lung function and sleep studies in DM have demonstrated a lack of correlation between symptoms and physiological parameters. A lower FVC tends to correlate with daytime hypercapnia but not sleep-disordered breathing, and DM patients with normal FVC can still have a significant degree of sleep apnoea.28 Other parameters such as symptoms of loud snoring, presence of hypertension, increased BMI and neck circumference are likely to be a useful guide to risk of obstructive sleep apnoea, but have not been studied in this patient population.29,30 Patients with myotonic dystrophy can develop daytime hypercapnia insidiously. The most common presenting symptom is excessive daytime somnolence.31,32 Hypercapnia correlates with the degree of overall muscular disability, inspiratory muscle

P. Robinson et al. weakness and FVC% predicted.31 A cohort study of 13 patients with myotonic dystrophy requiring NIV commenced therapy for those who had acute respiratory failure in the setting of an infective process, and for those who had symptomatic hypercapnia with daytime PaCO2 449 mmHg or nocturnal TcCO2 456 mmHg.32 The most common symptoms were of daytime sleepiness, exertional dyspnoea, morning headache and insomnia. Mean spirometry values at commencement of NIV in this study were FEV1 ¼ 1.27 L and FVC ¼ 1.66 L. Respiratory mouth muscle pressures were also reduced. There is a body of evidence that suggests that the excessive daytime somnolence in DM is not due to sleep apnoea or hypoventilation, but due to dysfunction of central sleep regulation. In a study of 22 DM patients, 17 of whom had hypersomnolence, polysomnography documented significant sleep-disordered breathing in only 5 patients, with central sleep apnoea seen in all 5 patients.33 Seventeen of these patients had excessive daytime sleepiness, and a majority of the group appeared to have a positive response to methylphenidate. There were also a large proportion of subjects who demonstrated periodic breathing. Other evidence supporting the role of a central cause of hypersomnolence in DM includes imaging studies showing specific abnormalities on neuroimaging, and necropsy studies showing loss of brainstem nuclei serotonergic neurons correlating with hypersomnolence.34–36 Finally, CSF hypocretin levels are decreased in DM1 patients with excessive daytime somnolence and no evidence of sleep-disordered breathing on sleep studies.37 A systematic metaanalysis found a small positive effect from Modafanil, but no beneficial effect from other psychostimulants.38–40 Validated measures of daytime sleepiness, such as the Epworth Sleepiness Scale, may not be a reliable measure of daytime sleepiness in DM patients, with other scales incorporating measures of fatigue demonstrating stronger internal consistency.41 As a result of this heterogeneity, our approach at initial consultation is to carefully probe for any symptoms, perform lying and sitting spirometry and arterial blood gases. Given the broad range of aetiologies for hypersomnolence, full polysomnography with transcutaneous carbon dioxide monitoring is important if this symptom is prominent.

MND No single static lung function test can predict the onset of hypercapnic respiratory failure in

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease MND. Given the rapidity with which hypercapnic respiratory failure may develop and its implications, frequent monitoring of symptoms and lung function is important. Studies in this area have demonstrated:













 

There is a strong correlation between transdiaphragmatic pressure (Pdi) and sniff nasal inspiratory force (SNIF). A SNIFo40 cmH2O was significantly correlated with nocturnal hypoxemia. When SNIF was o40 cmH2O, the hazard ratio for death was 9.1 (p ¼ 0.001), and the median survival was 670.3 months. The sensitivity of FVCo50% for predicting 6-month mortality was only 58% with a specificity of 96%, whereas SNIFo40 H2O had a sensitivity of 97% and a specificity of 79% for death within 6 months.42 Supine FVC, upright FVC, MIP, MEP, and Pdi–SNIF were significantly associated with tracheostomyfree survival after controlling for non-pulmonary factors, whereas PaCO2 was not. A normal supine FVC, MIP, or MEP was highly predictive for 1-year survival.43 Baseline FVC% predicted at an initial visit correlates with survival and rate of progression. FVCo75% predicted at baseline was associated with a median survival of 2.91 years compared to 4.08 years for those with FVC475% predicted.44 Sniff nasal pressure testing is a reliable and validated method of determining inspiratory muscle strength in MND. However, the optimal number of sniffs needed for reproducible results in patients with neuromuscular disease limits the utility of such testing.45–47 In MND patients without significant bulbar involvement, Pdi–SNIFo30 cmH2O had the greatest predictive power for the presence of daytime hypercapnia [odds ratio (OR) 57]. No test had a significant predictive power for daytime hypercapnia in patients with significant bulbar disease.45 This study also demonstrated a correlation between Pdi–SNIF and Apnoea– Hypopnoea Index (AHI) on polysomnography. A supine FVC% predicted o75% was highly sensitive and specific for the presence of diaphragm weakness when compared with the gold standard, Pdi. Pdi–SNIF also demonstrated a close linear correlation with FVC% predicted.47 Patients with MND and diaphragm weakness have reduced lung compliance which can be increased with brief supramaximal lung inflations.48 Quality of life in MND patients is correlated with measurements of respiratory muscle function, but not measures of sleep-disordered breathing.49

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Sleep studies in MND patients can demonstrate a range of abnormalities, including hypoventilation with increased TcCO2, obstructive sleep apnoea, which may be more likely in patients with bulbar disease, and sleep disruption.45 Our approach for MND patients is as follows: (1) Perform lying and sitting spirometry at each visit. Caution should be taken when interpreting FVC in this group of patients, as it is a volitional test and facial muscle weakness may affect results. Specific mouthpieces to accommodate facial weakness should be utilised. (2) When a difference of 420% decline in VC between sitting and lying positions is documented this suggests substantial diaphragmatic weakness and further testing of supine spirometry is not necessary at subsequent follow up. (3) Arterial blood gas assessment is performed when there is orthopnoea, asymptomatic diaphragm weakness on positional spirometry, or symptoms of hypercapnia (early morning headaches, sleep disruption, hypersomnolence). Additionally all patients undergoing a PEG insertion have arterial blood gases prior to the procedure. (4) We review our patients’ respiratory status every 3 months and encourage patients to contact the service should sleep-disordered breathing symptoms occur in the interim. (5) We reserve sleep studies for those with symptomatic daytime hypercapnia or orthopnoea in patients who have indicated willingness to trial NIV.

Non-invasive ventilation (NIV) Non-invasive ventilation has been available in various forms for many years. Earlier devices, however, were cumbersome and had significant limitations. Table 1 provides an outline of the general indications for NIV in patients with chronic neuromuscular disorders. Practical considerations are summarised in Table 2 and potential complications in Table 3. Nasal positive pressure ventilation was first described in 1984 in patients with DMD.50 With the development of portable NIV devices and increased availability of various interfaces, significant experience has been gained with use in patients with neuromuscular and chest wall diseases.51 Pooled data in chronic NMD has demonstrated NIV to be physiologically, symptomatically and practically effective, with survival benefits.

ARTICLE IN PRESS 242

P. Robinson et al.

Table 1 Indications for commencing NIV in chronic neuromuscular disorders. Primary indications (1) (2) (3) (4)

Orthopnoea Morning headache Excessive daytime somnolence Sleep disruption or frequent nocturnal wakening (5) Daytime fatigue

Table 2. (continued )

 Carers should be given specific education about how to apply each interface and should be available as a committed nocturnal carer  Weight loss can significantly effect facial soft tissue shape, and contribute to mask leak in an otherwise stable patient. When use of NIV increases to include daytime ventilation, a different interface should be considered to reduce likelihood of pressure areas

Other potential indications (1) During intercurrent chest infections, to aid with

sputum clearance and to prevent development of hypercapnia (2) Peri-operative respiratory support in patients with marginal respiratory reserve e.g. PEG placement (3) Palliation of dyspnoea

Table 2

Some practical aspects of starting NIV.

Table 3

Principal complications of NIV.

1. Pressure areas on nasal bridge and other facial 2. 3. 4. 5.

areas Eye irritation and conjunctivitis Aerophagia Emesis into a full face mask Chest wall discomfort

DMD

General points

 Easier to start electively rather than in an acute

 

 

situation, therefore monitoring of respiratory function and screening for sleep disordered breathing symptoms as an outpatient is important A period of acclimatization is useful Pressure settings will depend on degree of respiratory muscle weakness, presence of bulbar disease and upper airway obstruction, degree of lung and chest wall compliance A full-time nocturnal carer is often required and should be trained in the application and management of NIV for the home setting Patients requiring NIV for 414 h/day should have access to a backup power source and a second ventilator in case of equipment failure

Interface issues

 Nasal interfaces are often preferred by patients requiring daytime NIV, as they facilitate speech and sputum clearance. Rigid mouthpieces may be an alternative  Full-face masks (covering both nose and mouth) or nasal mask plus chinstrap or lip-tape are preferable for nocturnal non-invasive ventilation and patients with prominent facial weakness, as mouth leaks tend to reduce effectiveness of ventilation at night  When initiating NIV, use of a nasal bridge pressure dressing may help avoid nasal pressure areas

During the 1980s and early 1990s, published experience in DMD patients utilised various modalities of ventilation, including negative pressure body-ventilators (e.g. pneumobelt), NIV and invasive positive pressure ventilation via tracheostomy.52,53 Results were mixed but overall suggested a survival benefit with acceptable impact on patients and their carers. By the late 1990s, DMD cohort studies were published demonstrating a significant survival advantage with NIV.9,10,54 Subsequently, use has become more widely accepted by both physicians and patients. Consensus guidelines recommend that ventilatory support should be offered to DMD patients when there is evidence of sleep-related upper airway obstruction or chronic respiratory insufficiency.1 Studies have demonstrated a significant effect on survival, extending lifespan by years, with acceptable quality of life for patients using these devices.55 Other benefits include reduced hospitalisations and improved gas exchange with symptomatic improvement of sleep-disordered breathing and daytime hypercapnia. There are still a number of patients who are not offered this treatment, and some of this may be related to physicians perception that patients on long term NIV have a reduced quality of life.56,57 Two studies have looked at introducing NIV in DMD patients without daytime hypercapnia. A French study randomised DMD patients free of

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease

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daytime hypercapnia with FVC 20–50% of predicted values. Patients randomised to NIV had 6 h of treatment per night. Over a mean follow-up of 52 months, a larger proportion of the NIV group had died.58 The majority of deaths were due to retained tracheobronchial secretions; however, the NIV groups also had a higher incidence of left ventricular hypokinesia. The other study included patients with neuromuscular and chest wall diseases of varying causes.59 Patients were randomised to either nocturnal NIV or a control group if they were found to have nocturnal hypoventilation with daytime normocapnia. A number of preset criteria were included to allow patients from the control group to commence NIV. These included daytime hypercapnia, more than three chest infections per year, or uncontrolled symptoms of nocturnal hypoventilation. Seventy per cent of nocturnal hypoventilation patients met these criteria within 12 months, and 90% had met them within 2 years. Barotrauma has been reported rarely with NIV in DMD patients, with one case report of two DMD patients who were ventilated with a volumetargeted ventilator.60

life.61 Early studies in the mid 1990s demonstrated a promising effect of NIV on survival in MND patients.63 Subsequent studies looking at survival were prospective or retrospective observational cohort studies.64–66 MND patients with bulbar symptoms tend to tolerate NIV less than those without bulbar symptoms, and this effects survival.64,67 Some studies have suggested that rate of decline of lung function is lower in those who are able to tolerate NIV.65,67 A recent landmark randomised-controlled study in 41 MND patients was able to demonstrate a survival benefit of 205 days in MND patients without significant bulbar symptoms.21 More importantly, this study also found improved quality of life in all MND patients treated with NIV, which was maintained throughout most of the treatment period. The subset of patients with severe bulbar impairment did not have a significant survival benefit from NIV, but did have improved quality of life measures. Timing of introduction of NIV in this study was based on symptoms of daytime hypercapnia or orthopnoea with maximum inspiratory pressure less than 60% predicted.

Myotonic Dystrophy (DM)

Co-morbidities

Few studies have specifically looked at the use of NIV in myotonic dystrophy. Several factors create difficulties in establishing NIV in this group of patients. These include irregular respiratory drive, upper-airway obstruction, peripheral and facial muscle weakness, and intellectual and emotional problems. NIV in DM patients has demonstrated improved physiological parameters and improved daytime sleepiness and sleep quality.32 However, compliance with NIV in this group of patients is more likely to be reduced compared to other chronic neuromuscular disease patients. No controlled data are available to demonstrate improved life expectancy in DM patients treated with NIV; however, in the only published cohort study, 5 of 13 patients continued on NIV for 42 years.32 Our experience suggests that patients who are able to notice a symptomatic benefit are more likely to continue with treatment.

Management of co-morbidities is of utmost importance to preserve quality of life. The Intensivist should be aware of the common co-morbidities associated with each of these neuromuscular diseases (see Table 4). The potential for cardiac disease should be given special consideration, as it is the second most common cause of mortality in many congenital neuromuscular diseases.

MND NIV is used in MND to alleviate symptoms, improve quality of life and prolong survival.61,62 A prospective study of quality of life in MND patients on NIV demonstrated improved vitality scores compared to a control group, and no adverse effect on quality of

Cardiac disease Cardiomyopathy is common in DMD. The incidence increases with age, such that it is universal by adulthood. Consensus guidelines recommend that DMD patients have an echocardiogram and ECG at diagnosis, every 2 years to age ten, and annually after age ten.68 Echocardiography can be difficult to interpret in the presence of chest wall deformity, and ECG markers such as sinus tachycardia on ECG has been shown to be temporally related to the development of LV dysfunction.69 Management of DMD cardiomyopathy has also evolved considerably in recent years. Steroid therapy has been shown to delay the progressive decline in cardiac muscle function, and this effect appears to be sustained beyond the initial period of therapy.70 Perindopril has been shown to delay the onset and progression

ARTICLE IN PRESS 244 Table 4

P. Robinson et al.

Nutrition

Important co-morbidities.

Duchenne muscular dystrophy

Myotonic dystrophy

Motor neurone disease

Spinal deformity Cardiac disease

Cognitive impairment Attention disorders Hypersomnolence

Bulbar disease Depression

Vitamin D deficiency Malnutrition Obesity

Malnutrition

Diabetes mellitus Adrenal insufficiency Thyroid disease Hypogonadism Cardiac disease GI disease

 dysphagia,  constipation  gallbladder stones

 pseudoobstruction

Nutritional status is of considerable importance in patients with neuromuscular disease. Excessive weight can cause increased load on respiratory muscles, exacerbating hypoventilation, and cause carer burden by making transfers more difficult. Conversely, numerous studies have documented poor nutritional status as risk factors for morbidity in DMD and MND.78 Assessment of nutritional status is difficult in this population as loss of muscle mass, reduced physical activity and swallowing difficulties can impact upon overall nutrition. Standard markers such as body mass index (BMI) do not give a reliable indication of nutritional status, and tools incorporating the division of fat and muscle compartments are likely to give a more accurate picture of nutritional status.79 Determining nutritional requirements for patients with neuromuscular disease who require substantial proportions of time on NIV can be difficult. One mathematical model has suggested the following equation to determine total energy expenditure (TEE)80: TEE ¼ 0:54½66:47 þ 13:75ðweight in kilogramsÞ þ 5:00ðheight in centimetersÞ  6:76ðage in yearsÞ.

Cataracts

of left ventricular dysfunction in DMD.71 Subsequent studies have demonstrated improved left ventricular function with ACE inhibitors in combination with beta-blockers, while genetic predictors of cardiomyopathy have also been identified.72,73 No trials have demonstrated a survival benefit for any of these therapies in DMD, and treatment of asymptomatic myocardial dysfunction remains controversial.74 Cardiac disease is also a significant co-morbidity in DM. Arrhythmias are the most common cardiac manifestation in DM1, and can include atrial and ventricular arrhythmias and conduction abnormalities.75 The published cohort studies in DM populations demonstrate cardiac arrhythmia is the cause of death in 10–30% of patients.15,16 Guidelines therefore recommend an annual ECG in all DM patients from diagnosis.68 Another study of ECG changes in a DM cohort demonstrated that age of onset of ECG conduction abnormalities is inversely correlated with length of the trinucleotide repeat.76 Cardiac muscle dysfunction is infrequent and routine echocardiography is not recommended. DM2 has less frequent cardiac involvement, with the most common conduction abnormalities being first degree atrio-ventricular and bundle branch block.77

DMD Obesity from overfeeding and reduced physical activity levels is common during later childhood years in DMD; however, with progressive disability, malnutrition is more common by late teenage years. In one series, weight was normally distributed up until age 9, after which there was a disproportionate number of 9–13 year-olds above the 90th centile (44%), and also a disproportionate number below the 10th centile (65%) in those aged over 17 years.7 A retrospective study in DMD patients of varying ages looked at feeding and nutritional problems across age groups.81 Chewing and swallowing problems became progressively more common with age such that time taken to eat meals progressively increased; however, episodes of choking and aspiration pneumonia were uncommon, and more likely to occur in those aged 418 years. In stable DMD patients with advanced disease, resting energy expenditure is balanced with energy intake, suggesting that this group of patients are not at significant risk for malnutrition when clinically stable.82 Specific consideration should be given to the risk of starvation ketoacidosis and re-feeding syndrome, both of which we

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease have seen during acute infective exacerbations in the DMD patient population. Starvation ketoacidosis can be an important additional respiratory load during acute illness.

MND MND patients with bulbar symptoms will typically develop dysphagia and weight loss. Co-existent depression can also impact on appetite. In addition to this, resting energy expenditure has been shown to be increased in non-ventilated patients with MND by up to 10%.83 PEG feeding tube placement may improve nutritional status but evidence suggests it does not necessarily prolong life or prevent aspiration.84 Timing of insertion of PEG tubes is difficult, and depends upon presence of respiratory muscle weakness, amount and rate of weight loss, degree of swallowing difficulty and general health status of the patient. Guidelines suggest that PEG tubes should be placed prior to VC falling below 50% predicted.4,5 Thus, it is preferable, and probably safer, to place PEG feeding tubes prior to the development of hypercapnic respiratory failure. However, it has been demonstrated that PEG placement is possible and safe in patients already receiving NIV with VCo50% predicted.85,86 Physicians should also be aware that MND patients may be taking a range of nutritional supplements.87

Sputum clearance With the advent of non-invasive ventilation, more techniques and devices providing cough-augmentation therapy to support airway clearance have been developed, which are of vital importance in the prevention and treatment of bronchial secretions.85,88 Peak cough-flow (PCF) has been used as a measure of cough effectiveness in patients with neuromuscular disease and bulbar involvement, and is performed by asking the patient to take a full inspiration and cough forcibly through a mouthpiece or face mask attached to a peak flow metre.89 Values below 270 L/min are considered indicative of risk for URTI-associated respiratory failure due to ineffective cough, and PCFo160 L/min has been used as a cut-off for the introduction of a mechanical in-exsufflation device in a DMD cohort.90 PCF of o255 L/min has been associated with ineffective spontaneous cough during LRTI in MND patients.91 Clinical scores, such as the Norris Bulbar Score, have been validated as effective clinical tools to determine which patients with neuromuscular

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disease have poor bulbar function and therefore increased risk of ineffective cough and aspiration.91 Methods used to assist cough are well described, and include manual cough augmentation, hyperinflation manoeuvres, breath-stacking and mechanical insufflation–exsufflation devices. Combinations of these methods can be used in both acute and chronic settings. Use of a protocol consisting of monitoring oxyhaemoglobin saturations with pulse oximetry, adding NIV, assisted coughing techniques and mechanical in-exsufflation for acute episodes of desaturation or mucus retention have demonstrated a significant impact on hospitalisation rates and days of hospitalisation in previous retrospective cohort studies.55,90,92 Consensus guidelines are supportive of mechanical in-exsufflation devices despite the lack of randomised evidence.1

Management and prevention of acute lower respiratory tract infection Patients utilising non-invasive ventilation who develop symptoms and signs of acute lower respiratory tract infection require prompt treatment with appropriate antibiotic therapy. Consideration should be given to the potential role of aspiration as a cause of pneumonia. Guidelines recommend early antibiotic therapy, and it is often appropriate to ensure that the patient and carer have ready access to antibiotics, with clear written instructions provided for when to start these.3 Attention should be given to hydration status, and cautious intravenous fluid therapy should be considered in hospitalised patients. Sputum clearance is problematic in a dehydrated patient. Many patients will require additional periods of non-invasive ventilation use on top of their normal requirements, and should be instructed that this is both appropriate and desirable until such time as the acute infective episode is settling. Prevention of lower respiratory tract illness with Pneumococcal vaccination and influenza vaccination is also advised in guidelines; however, no randomised data exists within this patient population to demonstrate that this is efficacious.3

Corticosteroids Clinicians managing respiratory illness in patients with neuromuscular disease should ensure they have an understanding of the patient’s exposure to corticosteroids. In DMD, there is a considerable body of evidence for glucocorticoids to delay

ARTICLE IN PRESS 246 progression of disease and disability.93–102 Prednisone and deflazacort have both been shown to preserve ambulation, muscle function, respiratory function, cardiac function and prevent weight loss. Treatment is usually commenced prior to puberty, and evidence suggests continuing treatment for 6 months–2 years, however, many patients continue into late teenage and adult years. As many DMD patients have significant glucocorticoid exposure and reduced mobility, osteoporosis is a significant problem that requires attention in this group, as any rib or vertebral fractures are likely to cause further respiratory insult.103

End-of-life issues Providing sufficient information to patients and their families is critical in allowing advanced planning for end-of-life issues. As previously mentioned, physicians may underestimate the quality of life of patients with neuromuscular diseases, and may therefore avoid discussing available modalities of treatment.56 Written end-of-life directives can be a mechanism of raising issues relating to invasive ventilation via tracheostomy, artificial feeding and palliative care. This is also a useful time to introduce the concept of symptom control with pharmacotherapy and referral to a palliative care service. Many patients will take some comfort in the advanced awareness of use of opioids, benzodiazepines and other drugs for palliation of symptoms such as dyspnoea and anxiety. Clinicians should also enquire about legal matters such as completion of a Will and Enduring Power of Attorney. Withdrawal of respiratory support should be discussed with the patient if they are in a position to comprehend their own situation.104

Tracheostomy and invasive ventilation The decision to invasively ventilate a patient with a progressive neuromuscular disease is difficult, and must be carefully considered in view of the patient’s degree of disability, social supports and availability of 24-h nursing care should permanent tracheostomy and IPPV be necessary. One study in DMD has looked at the viability of using 24-h NIV via rigid mouthpiece during the day with nasal interface overnight.105 Considerable debate continues regarding the appropriateness of tracheostomy in patients with progressive neuromuscular disease, and open informed discussions should occur with patients and their families prior to deciding on the

P. Robinson et al. most appropriate course of action.106–108 Discussions should include the degree of training required for the patient, carers and nursing staff, initial and ongoing cost of equipment, and availability of appropriate accommodation. Local factors such as expertise in non-invasive ventilation and home ventilation via tracheostomy should also be considered. Quality of life in MND patients treated with tracheostomy is reduced compared to those using nasal positive pressure ventilation.109 Open discussions regarding the advantages and disadvantages of tracheostomy and invasive ventilation should occur as the disease progresses and/or with hospitalisations. The main advantages include provision of a more secure ventilator–patient interface and the ability to provide higher ventilator pressures. Disadvantages include increased secretions and infections, impairment of swallow and vocalisation, tracheoesophageal fistula, tracheal stenosis, tracheomalacia and increased nursing and carer requirements. Aspiration remains a problem with both NIV and invasive ventilation.4

Perspective of patients and carers One group has surveyed patient preference for invasive versus non-invasive ventilation in a group of 168 patients who had experienced both tracheostomy and non-invasive ventilation for at least 1 month.110 Many patients had used negative pressure body ventilators, although a proportion had used NIV. Overall, patients and caregivers preferred non-invasive forms of ventilation, citing ability to speak, appearance and reduced discomfort as the main reasons. Reasons for preferring ventilation via tracheostomy included increased ability to sleep and security. A quality of life survey of ventilator-dependent DMD patients found that most were satisfied with their quality of life despite the hardships associated with home mechanical ventilation.57 Health care professionals significantly underestimated the quality of life of these individuals. Involvement of patients and their families in decision-making is critical when considering longterm ventilation. Clinicians should aim to educate the patient and their family prior to the decision to institute any form of ventilation. It is also important to provide ongoing education and psychological support for these patients and families, such as that provided through specialised clinics for DMD patients.111 Clear information should be provided about other palliative options for those who do not wish to consider NIV. Consideration should also be

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease given to the availability of respite for carers, as carer burden is a significant issue.

Strategies to assist patients admitted to ICU with exacerbations of respiratory failure Admission to intensive care may offer patients a number of advantages. These include a higher acuity of nursing care, increased available physiotherapy treatment time to facilitate clearance of secretions and more sophisticated invasive or non-invasive ventilators. Small benefits may be obtained from adjunctive therapies that together may lead to morbidity and mortality improvements, although data pertaining to patients with chronic neuromuscular disorders, requiring ICU management is lacking. Reversible contributions to the exacerbation of respiratory failure should be actively sought and treated such as infection, decompensated heart failure and pulmonary embolism. A trial of various therapies may be attempted and tailored to the individuals’ response. Humidification of inspired gases may improve secretion expectoration, however, the sensation of breathing warmed gases is not always well tolerated. In these patients, nebulised saline may be of some benefit. Inhaled N-acetylcysteine (mucomyst) has no proven benefit and cause epithelial damage.112 Meticulous attention should be given to fluid and electrolyte status, with avoidance of dehydration and more importantly fluid overload and electrolyte disorders. Judicious and carefully selected diuretics may be administered if elements of fluid overload and pulmonary oedema are suspected. Metabolic alkalosis, seen commonly with loop diuretics such as frusemide, should be avoided, as it may precipitate a compensatory respiratory acidosis with worsening hypercapnia. Hypokalaemia and hypophosphataemia are common sideeffects that can exacerbate muscle weakness. Rapid administration of intravenous magnesium sulphate may cause transient profound weakness and vasodilatation. Successful improvement in hypercapnic respiratory failure with metabolic alkalosis has been reported with acetazolamide that superimposes a metabolic acidosis.113 Hyperoxia should be avoided in patients with type 2 respiratory failure that are dependent on hypoxic ventilatory drive. Care should be taken in ensuring that adequate doses of stress steroids should be provided to

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patients receiving chronic steroid therapy, usually for their anabolic effects. Abnormalities have been reported in the hypothalamic–pituitary–adrenal axis function of patients with DM compared to normal controls114 and various endocrine abnormalities including Addison’s disease have been reported.115 Endocrine causes of hypotension should be considered high in the differential diagnosis of distributive shock. Adequate nutrition should be provided. Artificial feeds with low respiratory quotients (e.g. high fat, low carbohydrate content) offer the theoretical benefit of generating a relatively reduced CO2 load on the respiratory system.116 Overfeeding, with excess CO2 production, may exacerbate hypercapnic respiratory failure in patients without ventilatory reserve.117 More concentrated feeds offer the advantage of a reduced goal-feeding rate. This means a reduced total volume of nutrition that needs to be consumed/delivered. The risks of aspiration in patients receiving full enteral feeding, particularly those receiving NIV or with bulbar dysfunction are considerable. Transpyloric feeding tubes may reduce this risk, however, their insertion may be problematic and require unwanted interventions such as interventional radiology and/or endoscopy.118 Total parenteral nutrition may be a short-term solution to patients who are at the highest risk of aspiration who are expected to recover from the acute exacerbation and wish this to be provided. A high and predictable risk of refeeding syndrome exists for individuals with chronically poor caloric intakes who have rapid restoration of goal calories with artificial nutrition.119 This life-threatening complication is heralded by hypokalaemia, hypomagnesaemia and hypophosphataemia may cause profound weakness with dramatic respiratory crises. For this reason, cautious, monitored, step-wise escalation of feeding rates should be prescribed. Antibiotic management for infection should be broad-spectrum and cover known colonising pathogens. The aminoglycoside class of antibacterials are implicated in causing critical illness polyneuromyopathy, particularly in concert with steroids and sepsis,120 and are accordingly best avoided. Of interest, however, is recent and ongoing work looking at gentamicin as a novel therapy for DMD. A subset of DMD patients has a non-sense mutation in their dystrophin gene causing premature termination of dystrophin translation. Gentamicin may suppress truncation of the protein and suppress the phenotypic manifestations of the disease.121 Early and ongoing open communication with the patient and their family, in consultation with the usual treating respiratory physician, should foster

ARTICLE IN PRESS 248 trust, and the development of realistic and desirable treatment goals. Classification should be made early regarding the relevance of a trial of invasive ventilation, performance of a tracheostomy, longterm ventilation and palliative care.

Conclusion Non-invasive ventilation is now widely used for a variety of chronic neuromuscular diseases, and available evidence demonstrates improved quality and quantity of life. Clinicians should be aware of the natural history of each neuromuscular disorder in order to make informed decisions about lifeprolonging therapies in the intensive care setting. Use of lying and sitting spirometry, and clinical assessment for sleep-disordered breathing and daytime hypercapnia are important factors when considering when to introduce non-invasive ventilation. Patient education regarding early management of respiratory tract infection and prevention thereof is of utmost importance. Attention to comorbidities and particularly cardiac status are important given that these are often treatable. Nutritional factors play an important role in patients receiving NIV, with malnutrition and obesity both providing specific challenges. End of life planning should be discussed with all patients requiring non-invasive ventilation.

References 1. Finder JD, Birnkrant D, Carl J, Farber HJ, Gozal D, Iannaccone ST, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170(4):456–65. 2. Heffernan C, Jenkinson C, Holmes T, Macleod H, Kinnear W, Oliver D, et al. Management of respiration in MND/ALS patients: an evidence based review. Amyotroph Lateral Scler 2006;7(1):5–15. 3. Shahrizaila T, Kinnear W. Recommendations for respiratory care of adults with muscle disorders. Neuromuscul Disord 2007;17(1):13–5. 4. Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe K, Leigh PN, et al. EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol 2005; 12(12):921–38. 5. Miller RG, Rosenberg JA, Gelinas DF, Mitsumoto H, Newman D, Sufit R, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidencebased review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 1999;52(7):1311–23. 6. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord 1991;1(1):19–29.

P. Robinson et al. 7. McDonald CM, Abresch RT, Carter GT, Fowler Jr WM, Johnson ER, Kilmer DD. Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil 1995;74(5 Suppl.):S70–92. 8. Calvert LD, McKeever TM, Kinnear WJ, Britton JR. Trends in survival from muscular dystrophy in England and Wales and impact on respiratory services. Respir Med 2006;100(6): 1058–63. 9. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 2002; 12(10):926–9. 10. Vianello A, Bevilacqua M, Salvador V, Cardaioli C, Vincenti E. Long-term nasal intermittent positive pressure ventilation in advanced Duchenne’s muscular dystrophy. Chest 1994;105(2):445–8. 11. Jeppesen J, Green A, Steffensen BF, Rahbek J. The Duchenne muscular dystrophy population in Denmark, 1977–2001: prevalence, incidence and survival in relation to the introduction of ventilator use. Neuromuscul Disord 2003;13(10):804–12. 12. Meola G. Myotonic dystrophies. Curr Opin Neurol 2000; 13(5):519–25. 13. Gagnon C, Noreau L, Moxley RT, Laberge L, Jean S, Richer L, et al. Towards an integrative approach to the management of myotonic dystrophy type 1. J Neurol Neurosurg Psychiatry 2007;78(8):800–6. 14. Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve 2005;32(1):1–18. 15. Mathieu J, Allard P, Potvin L, Prevost C, Begin P. A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology 1999;52(8):1658–62. 16. de Die-Smulders CE, Howeler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, et al. Age and causes of death in adultonset myotonic dystrophy. Brain 1998;121(Part 8):1557–63. 17. Chio A, Mora G, Leone M, Mazzini L, Cocito D, Giordana MT, et al. Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 2002;59(1):99–103. 18. Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 2006;66(2):265–7. 19. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994;330(9):585–91. 20. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2007(1):CD001447. 21. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5(2):140–7. 22. Shoesmith CL, Findlater K, Rowe A, Strong MJ. Prognosis of amyotrophic lateral sclerosis with respiratory onset. J Neurol Neurosurg Psychiatry 2007;78(6):629–31. 23. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med 2001;164(12):2191–4. 24. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;161(1):166–70.

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease 25. Smith PE, Edwards RH, Calverley PM. Ventilation and breathing pattern during sleep in Duchenne muscular dystrophy. Chest 1989;96(6):1346–51. 26. Barbe F, Quera-Salva MA, McCann C, Gajdos P, Raphael JC, de Lattre J, et al. Sleep-related respiratory disturbances in patients with Duchenne muscular dystrophy. Eur Respir J 1994;7(8):1403–8. 27. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19(6):1194–201. 28. Kumar SP, Sword D, Petty RK, Banham SW, Patel KR. Assessment of sleep studies in myotonic dystrophy. Chron Respir Dis 2007;4(1):15–8. 29. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5 Part 1): 1279–85. 30. Flemons WW. Clinical practice. Obstructive sleep apnea. N Engl J Med 2002;347(7):498–504. 31. Begin P, Mathieu J, Almirall J, Grassino A. Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 1997;156(1):133–9. 32. Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest 2002;121(2):459–64. 33. van der Meche FG, Bogaard JM, van der Sluys JC, Schimsheimer RJ, Ververs CC, Busch HF. Daytime sleep in myotonic dystrophy is not caused by sleep apnoea. J Neurol Neurosurg Psychiatry 1994;57(5):626–8. 34. Ono S, Kanda F, Takahashi K, Fukuoka Y, Jinnai K, Kurisaki H, et al. Neuronal loss in the medullary reticular formation in myotonic dystrophy: a clinicopathological study. Neurology 1996;46(1):228–31. 35. Giubilei F, Antonini G, Bastianello S, Morino S, Paolillo A, Fiorelli M, et al. Excessive daytime sleepiness in myotonic dystrophy. J Neurol Sci 1999;164(1):60–3. 36. Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, et al. Loss of serotonin-containing neurons in the raphe of patients with myotonic dystrophy: a quantitative immunohistochemical study and relation to hypersomnia. Neurology 1998;50(2):535–8. 37. Martinez-Rodriguez JE, Lin L, Iranzo A, Genis D, Marti MJ, Santamaria J, et al. Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 2003; 26(3):287–90. 38. Damian MS, Gerlach A, Schmidt F, Lehmann E, Reichmann H. Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology 2001;56(6):794–6. 39. MacDonald JR, Hill JD, Tarnopolsky MA. Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy. Neurology 2002;59(12):1876–80. 40. Annane D, Moore DH, Barnes PR, Miller RG. Psychostimulants for hypersomnia (excessive daytime sleepiness) in myotonic dystrophy. Cochrane Database Syst Rev 2006;3: CD003218. 41. Laberge L, Gagnon C, Jean S, Mathieu J. Fatigue and daytime sleepiness rating scales in myotonic dystrophy: a study of reliability. J Neurol Neurosurg Psychiatry 2005; 76(10):1403–5. 42. Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2005;171(3):269–74. 43. Schmidt EP, Drachman DB, Wiener CM, Clawson L, Kimball R, Lechtzin N. Pulmonary predictors of survival in

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

249

amyotrophic lateral sclerosis: use in clinical trial design. Muscle Nerve 2006;33(1):127–32. Czaplinski A, Yen AA, Appel SH. Forced vital capacity (FVC) as an indicator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 2006; 77(3):390–2. Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J. Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis. Brain 2001;124(Part 10): 2000–13. Lofaso F, Nicot F, Lejaille M, Falaize L, Louis A, Clement A, et al. Sniff nasal inspiratory pressure: what is the optimal number of sniffs? Eur Respir J 2006;27(5):980–2. Lechtzin N, Wiener CM, Shade DM, Clawson L, Diette GB. Spirometry in the supine position improves the detection of diaphragmatic weakness in patients with amyotrophic lateral sclerosis. Chest 2002;121(2):436–42. Lechtzin N, Shade D, Clawson L, Wiener CM. Supramaximal inflation improves lung compliance in subjects with amyotrophic lateral sclerosis. Chest 2006;129(5):1322–9. Bourke SC, Shaw PJ, Gibson GJ. Respiratory function vs sleep-disordered breathing as predictors of QOL in ALS. Neurology 2001;57(11):2040–4. Delaubier A. Traitement de l’insuffisance respiratoire chronique dans les dystrophies musculaires. In: Memoires de certificat d’etudes superieures de reeducation et readaptation fonctionnelles [Dissertation]. Paris: Universite R Descarte; 1984. p. 1–124. Leger P, Bedicam JM, Cornette A, Reybet-Degat O, Langevin B, Polu JM, et al. Nasal intermittent positive pressure ventilation. Long-term follow-up in patients with severe chronic respiratory insufficiency. Chest 1994; 105(1):100–5. Mohr CH, Hill NS. Long-term follow-up of nocturnal ventilatory assistance in patients with respiratory failure due to Duchenne-type muscular dystrophy. Chest 1990; 97(1):91–6. Baydur A, Gilgoff I, Prentice W, Carlson M, Fischer DA. Decline in respiratory function and experience with longterm assisted ventilation in advanced Duchenne’s muscular dystrophy. Chest 1990;97(4):884–9. Simonds AK, Muntoni F, Heather S, Fielding S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998;53(11):949–52. Gomez-Merino E, Bach JR. Duchenne muscular dystrophy: prolongation of life by noninvasive ventilation and mechanically assisted coughing. Am J Phys Med Rehabil 2002;81(6):411–5. Gibson B. Long-term ventilation for patients with Duchenne muscular dystrophy: physicians’ beliefs and practices. Chest 2001;119(3):940–6. Bach JR, Campagnolo DI, Hoeman S. Life satisfaction of individuals with Duchenne muscular dystrophy using longterm mechanical ventilatory support. Am J Phys Med Rehabil 1991;70(3):129–35. Raphael JC, Chevret S, Chastang C, Bouvet F. Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French multicentre cooperative group on home mechanical ventilation assistance in Duchenne de Boulogne muscular dystrophy. Lancet 1994;343(8913): 1600–4. Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005;60(12):1019–24.

ARTICLE IN PRESS 250 60. Vianello A, Arcaro G, Gallan F, Ori C, Bevilacqua M. Pneumothorax associated with long-term non-invasive positive pressure ventilation in Duchenne muscular dystrophy. Neuromuscul Disord 2004;14(6):353–5. 61. Lyall RA, Donaldson N, Fleming T, Wood C, Newsom-Davis I, Polkey MI, et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 2001;57(1):153–6. 62. Piepers S, van den Berg JP, Kalmijn S, van der Pol WL, Wokke JH, Lindeman E, et al. Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature. Amyotroph Lateral Scler 2006;7(4):195–200. 63. Pinto AC, Evangelista T, Carvalho M, Alves MA, Sales Luis ML. Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial. J Neurol Sci 1995;129(Suppl.):19–26. 64. Aboussouan LS, Khan SU, Meeker DP, Stelmach K, Mitsumoto H. Effect of noninvasive positive-pressure ventilation on survival in amyotrophic lateral sclerosis. Ann Intern Med 1997;127(6):450–3. 65. Kleopa KA, Sherman M, Neal B, Romano GJ, HeimanPatterson T. Bipap improves survival and rate of pulmonary function decline in patients with ALS. J Neurol Sci 1999;164(1):82–8. 66. Bach JR. Amyotrophic lateral sclerosis: prolongation of life by noninvasive respiratory AIDS. Chest 2002;122(1):92–8. 67. Lo Coco D, Marchese S, Pesco MC, La Bella V, Piccoli F, Lo Coco A. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival. Neurology 2006;67(5): 761–5. 68. Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy, 7–9 June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003;13(2):166–72. 69. Markham LW, Barone A, Kinnett K, et al. Revising the cardiac phenotype of Duchenne muscular dystrophy. Neuromuscul Disord 2006;16:699. 70. Markham LW, Spicer RL, Khoury PR, Wong BL, Mathews KD, Cripe LH. Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr Cardiol 2005;26(6): 768–71. 71. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005;45(6): 855–7. 72. Kajimoto H, Ishigaki K, Okumura K, Tomimatsu H, Nakazawa M, Saito K, et al. Beta-blocker therapy for cardiac dysfunction in patients with muscular dystrophy. Circ J 2006;70(8):991–4. 73. Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005;112(18):2799–804. 74. English KM, Gibbs JL. Cardiac monitoring and treatment for children and adolescents with neuromuscular disorders. Dev Med Child Neurol 2006;48(3):231–5. 75. Pelargonio G, Dello Russo A, Sanna T, De Martino G, Bellocci F. Myotonic dystrophy and the heart. Heart 2002;88(6): 665–70. 76. Antonini G, Giubilei F, Mammarella A, Amicucci P, Fiorelli M, Gragnani F, et al. Natural history of cardiac involvement in myotonic dystrophy: correlation with CTG repeats. Neurology 2000;55(8):1207–9.

P. Robinson et al. 77. Meola G, Moxley III RT. Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 2004;251(10): 1173–82. 78. Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Nutritional status is a prognostic factor for survival in ALS patients. Neurology 1999;53(5):1059–63. 79. Pessolano FA, Suarez AA, Monteiro SG, Mesa L, Dubrovsky A, Roncoroni AJ, et al. Nutritional assessment of patients with neuromuscular diseases. Am J Phys Med Rehabil 2003; 82(3):182–5. 80. Munn MW. Estimate of daily calorie needs for a neuromuscular disease patient receiving noninvasive ventilation. Am J Phys Med Rehabil 2005;84(8):639–43. 81. Pane M, Vasta I, Messina S, Sorleti D, Aloysius A, Sciarra F, et al. Feeding problems and weight gain in Duchenne muscular dystrophy. Eur J Paediatr Neurol 2006;10(5–6): 231–6. 82. Gonzalez-Bermejo J, Lofaso F, Falaize L, Lejaille M, Raphael JC, Similowski T, et al. Resting energy expenditure in Duchenne patients using home mechanical ventilation. Eur Respir J 2005;25(4):682–7. 83. Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrere B, et al. Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr 2001;74(3):328–34. 84. Heffernan C, Jenkinson C, Holmes T, Feder G, Kupfer R, Leigh PN, et al. Nutritional management in MND/ALS patients: an evidence based review. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5(2):72–83. 85. Boitano LJ, Jordan T, Benditt JO. Noninvasive ventilation allows gastrostomy tube placement in patients with advanced ALS. Neurology 2001;56(3):413–4. 86. Gregory S, Siderowf A, Golaszewski AL, McCluskey L. Gastrostomy insertion in ALS patients with low vital capacity: respiratory support and survival. Neurology 2002;58(3):485–7. 87. Cameron A, Rosenfeld J. Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders. Curr Opin Clin Nutr Metab Care 2002;5(6):631–43. 88. Bach JR. Update and perspective on noninvasive respiratory muscle aids. Part 2: the expiratory aids. Chest 1994;105(5):1538–44. 89. Suarez AA, Pessolano FA, Monteiro SG, Ferreyra G, Capria ME, Mesa L, et al. Peak flow and peak cough flow in the evaluation of expiratory muscle weakness and bulbar impairment in patients with neuromuscular disease. Am J Phys Med Rehabil 2002;81(7):506–11. 90. Bach JR, Ishikawa Y, Kim H. Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1997;112(4):1024–8. 91. Sancho J, Servera E, Diaz J, Marin J. Predictors of ineffective cough during a chest infection in patients with stable amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2007;175(12):1266–71. 92. Tzeng AC, Bach JR. Prevention of pulmonary morbidity for patients with neuromuscular disease. Chest 2000;118(5): 1390–6. 93. Mendell JR, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller JP, et al. Randomized, double-blind six-month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med 1989;320(24):1592–7. 94. Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am J Phys Med Rehabil 2005;84(11):843–50.

ARTICLE IN PRESS Respiratory management of adult patients with progressive neuromuscular disease 95. Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 2006;16(4):249–55. 96. Bonifati MD, Ruzza G, Bonometto P, Berardinelli A, Gorni K, Orcesi S, et al. A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 2000;23(9):1344–7. 97. Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids, 2–4 April 2004, Naarden, The Netherlands. Neuromuscul Disord 2004;14(8–9):526–34. 98. Campbell C, Jacob P. Deflazacort for the treatment of Duchenne Dystrophy: a systematic review. BMC Neurol 2003;3:7. 99. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2004(2):CD003725. 100. Moxley III RT, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64(1):13–20. 101. Pradhan S, Ghosh D, Srivastava NK, Kumar A, Mittal B, Pandey CM, et al. Prednisolone in Duchenne muscular dystrophy with imminent loss of ambulation. J Neurol 2006;253(10):1309–16. 102. Griggs RC, Moxley III RT, Mendell JR, Fenichel GM, Brooke MH, Pestronk A, et al. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol 1991;48(4):383–8. 103. Quinlivan R, Roper H, Davie M, Shaw NJ, McDonagh J, Bushby K. Report of a Muscular Dystrophy Campaign funded workshop Birmingham, UK, January 16, 2004. Osteoporosis in Duchenne muscular dystrophy; its prevalence, treatment and prevention. Neuromuscul Disord 2005;15(1):72–9. 104. Nava S, Sturani C, Hartl S, Magni G, Ciontu M, Corrado A, et al. End-of-life decision-making in respiratory intermediate care units: a European survey. Eur Respir J 2007;30(1):156–64. 105. Toussaint M, Steens M, Wasteels G, Soudon P. Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients. Eur Respir J 2006;28(3):549–55. 106. Lofaso F, Orlikowski D, Raphael JC. Ventilatory assistance in patients with Duchenne muscular dystrophy. Eur Respir J 2006;28(3):468–9.

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107. Bach JR, Bianchi C, Finder J, Fragasso T, Goncalves MR, Ishikawa Y, et al. Tracheostomy tubes are not needed for Duchenne muscular dystrophy. Eur Respir J 2007;30(1): 179–80 [author reply 180–1]. 108. Lofaso F, Orlikowski D, Raphael J-C. From the authors. Eur Respir J 2007;30:180–1. 109. Cazzolli PA, Oppenheimer EA. Home mechanical ventilation for amyotrophic lateral sclerosis: nasal compared to tracheostomy-intermittent positive pressure ventilation. J Neurol Sci 1996;139(Suppl.):123–8. 110. Bach JR. A comparison of long-term ventilatory support alternatives from the perspective of the patient and care giver. Chest 1993;104(6):1702–6. 111. Gilgoff I, Prentice W, Baydur A. Patient and family participation in the management of respiratory failure in Duchenne’s muscular dystrophy. Chest 1989;95(3): 519–24. 112. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respir Care 2007;52(7):859–65. 113. Webster NR, Kulkarni V. Metabolic alkalosis in the critically ill. Crit Rev Clin Lab Sci 1999;36(5):497–510. 114. Hockings GI, Grice JE, Crosbie GV, Walters MM, Jackson RV. Altered hypothalamic-pituitary-adrenal axis responsiveness in myotonic dystrophy: in vivo evidence for abnormal dihydropyridine-insensitive calcium transport. J Clin Endocrinol Metab 1993;76(6):1433–8. 115. Zargar AH, Bhat MH, Ganie MA, Laway BA, Masoodi SR, Salahuddin M, et al., editors. Polyglandular endocrinopathy in myotonic dystrophy: letter to editor. Neurol India 2002;50(1):105–6. 116. Cai B, Zhu Y, Ma Y, Xu Z, Zao Y, Wang J, et al. Effect of supplementing a high-fat, low-carbohydrate enteral formula in COPD patients. Nutrition 2003;19(3): 229–32. 117. Reid C. Frequency of under- and overfeeding in mechanically ventilated ICU patients: causes and possible consequences. J Hum Nutr Diet 2006;19(1):13–22. 118. Stone SJ, Pickett JD, Jesurum JT. Bedside placement of postpyloric feeding tubes. AACN Clin Issues 2000;11(4): 517–30. 119. Marinella MA. The refeeding syndrome and hypophosphatemia. Nutr Rev 2003;61(9):320–3. 120. Kane SL, Dasta JF. Clinical outcomes of critical illness polyneuropathy. Pharmacotherapy 2002;22(3): 373–9. 121. Wagner KR, Hamed S, Hadley DW, Gropman AL, Burstein AH, Escolar DM, et al. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol 2001;49(6):706–11.