**3. Non-invasive mechanical ventilation**

Long-term mechanical ventilation in patients with neuromuscular problems was first introduced between 1950 and 1960 in France and Sweden as a consequence of the poliomyelitis epidemics. During the following decades, the concept of home mechanical ventilation expanded rapidly, and long-term non-invasive positive-pressure ventilation (NIPPV) was implemented in many other countries and for many other conditions, including ALS, to treat chronic alveolar hypoventilation.

Chronic alveolar hypoventilation is a state characterized by reduced arterial oxygen tension and increased carbon dioxide tension, which the patient may correct at least partially by voluntary hyperventilation. The underlying mechanisms are not yet fully understood and may involve impairment of lung mechanics or airway function and cough, ventilationperfusion mismatch, blunted central ventilatory drive, or respiratory muscle fatigue. Abnormalities may occur while awake or during sleep. In most cases, chronic alveolar hypoventilation leads to daytime fatigue, hypersomnia, and changes in psychological function.

The application of ventilatory assistance in ALS, most frequently non-invasively, has led in the last fifteen years to a revolution in respiratory assistance and ventilatory support in these patients, with a significant impact on the natural history of the disorder. Indeed, NIPPV has been shown to alleviate respiratory symptoms, to extend survival considerably,

Assessment and Management of

et al., 1998; Gay & Edmonds, 1995).

(Radunović et al., 2007; Miller et al., 2009a).

**4. Physiotherapy and management of airway secretions** 

problematic, leading to further pulmonary complications.

Respiratory Dysfunction in Patients with Amyotrophic Lateral Sclerosis 583

et al., 2009a). Indeed, the increased risk of aspiration in patients with bulbar onset and problems because of difficulties in clearing secretions or obstructions, such as those related

In our experience NIPPV can be well tolerated by both patients and caregivers, even in patients with bulbar involvement, especially if an intensive educational training and adaptation on NIPPV can be performed (Volanti et al., 2011). Special importance, then, should be deserved to adaptation and compliance during the first few weeks of NIPPV use,

Factors predicting survival following NIPPV include advanced age, airway mucus accumulation and lower body mass index (Peysson et al., 2008; Lo Coco et al., 2006). Noncompliance with NIPPV has been related to frontotemporal dysfunction and severe bulbar involvement, whereas compliance with the treatment was associated with young age, preserved upper limb function, symptoms of orthopnea and dyspnea, use of percutaneous endoscopic gastrostomy (PEG), speech devices, and riluzole (Bourke et al., 2003, 2006; Gruis et al., 2005; Olney et al., 2005; Jackson et al., 2006). Nocturnal hypercapnea has also been recently indicated as a predictor of good compliance with subsequent NIPPV treatment (Kim et al., 2011). Oxygen supplementation should be avoided unless provided with mechanical ventilation or to treat dyspnea as a palliative, periodically monitoring CO2 levels. In fact oxygen therapy may reduce respiratory drive particularly during sleep and has been associated with CO2 retention and a less favourable outcome than ventilation (Bach

At present, worldwide accepted guidelines propose NIPPV initiation in the presence of respiratory symptoms, and/or evidence of respiratory muscles weakness (FVC ≤ 80% of predicted or SNIP ≤ 40 cmH2O), evidence of significant nocturnal desaturation on overnight oximetry (< 90% for > 5% of the time asleep) or a morning arterial PaCO2 > 6.5 kPa

Physiotherapy is a useful palliative adjunction in the treatment on ALS, in particular in the management of respiratory secretions (Lo Coco et al., 2008). Indeed, during the course of the disease progressive inspiratory and expiratory muscle weakness and bulbar innervated muscle dysfunction result in ineffective cough reflex. Coughing, an important part of the airway defence aiding in the removal of secretions, consists of three components: an inspiratory phase, a compressive phase with glottic closure, and an expulsive phase resulting from sudden glottic opening. Patients with ALS may develop impairment of any of these three phases, and as a result, clearance of respiratory secretions may become

The effectiveness of mucus clearance is largely dependent on the magnitude of peak cough flows (PCFs) (King et al., 1985), which can be measured using a standard peak flow meter adapted to an anesthesia face mask. A PCF of < 2.7 L/s has been suggested to indicate an ineffective cough (Bach & Saporito, 1996; Tzeng & Bach, 2000). However, since PCF decreases during respiratory tract infections, when the pressure generated by expiratory muscles is reduced (Poponick et al., 1997), it has been suggested that once a patient's PCF is < 4.5 L/s, particularly in the presence of bulbar dysfunction, there is a risk for pulmonary complications (Bach et al., 1997; Sancho et al., 2007). That threshold could be an appropriate time to implement assisted cough techniques. Moreover, patients with a mean PCF above

to abnormal function of the vocal cords, should be considered.

since this could be a crucial step in determining the efficacy of the treatment.

and to improve quality of life and cognitive functions in most patients (Miller et al., 2009a). At present time, NIV, usually via nasal mask with Bi-level Positive Airway Pressure (BiPAP) machines, is the most effective treatment available for ALS patients (Heiman-Patterson & Miller, 2006).

The first study that investigated the effects of NIPPV in patients with ALS dates back to 1995. In a non-randomized trial of NIPPV, Pinto and colleagues showed that survival was significantly longer in the nine patients that received NIPPV compared to the nine patients that received standard care (Pinto et al., 1995). In the following years, many cohort and retrospective studies, and a single randomized trial confirmed these results in those patients that used the ventilatory device for more than 4 hours/night (defined as tolerant patients) (Aboussouan et al., 1997, 2001; Kleopa et al., 1999; Bourke et al., 2003, 2006; Farrero et al., 2005; Gruis et al., 2005; Lo Coco et al., 2006b). In general, these studies demonstrated a median survival of 10 to 15 months in those who were able to tolerate NIPPV. It was also pointed out that NIPPV treatment could slow the rate of respiratory impairment, while severe bulbar impairment could affect NIPPV tolerance (Pinto et al., 1995; Aboussouan et al., 1997, 2001; Kleopa et al., 1999; Bourke et al., 2003, 2006; Farrero et al., 2005; Gruis et al., 2005; Lo Coco et al., 2006b). Furthermore, many recent studies showed that NIPPV therapy could improve quality of life of patients with ALS (Gelinas et al., 1998; Lyall et al., 2001a; Kaub-Wittemer et al., 2003; Bourke et al., 2003, 2006; Mustfa et al., 2006), although some suggested that the caregivers' burden could become heavier (Gelinas et al., 1998; Kaub-Wittemer et al., 2003). Finally, it has been reported that mechanical ventilation could improve cognitive function after some months of treatment (Newson-Davis et al., 2001).

Notwithstanding the aforementioned effects on respiratory symptoms, quality of life, and survival many studies suggest that the employment of NIPPV in ALS is poor worldwide (Bourke et al., 2002; Lechtzin et al., 2004), with a need for more education of clinicians and patients regarding the benefits of mechanical ventilation earlier in the course of the disease (Bradley et al., 2001). The reasons for such low uptake of NIPPV treatment are multifactorial but are influenced by differences in the experience of physicians, its availability and cost, uncertainty of the benefits and timing for starting ventilation, and concerns that ventilatory support might prolong suffering, render home care less feasible, and lead to dependency or ventilator entrapment (Radunović et al., 2007).

Moreover, there is still debate about the optimal timing to introduce ventilation in these patients and whether early NIPPV initiation could actually lead to increased survival rates. With regard to the first aspect, as previously discussed, there are at present many different guidelines that suggest numerous exams to be performed, including upright and supine spirometry, nocturnal oximetry, blood gas analysis and MIP (Andersen et al., 2005, 2007; Miller et al., 2009a).

Concerning to the effects of early NIPPV introduction in patients with ALS, there are some studies that reported increased compliance, quality of life and survival in those patients that received earlier treatment (mainly defined by the evidence of significant desaturations at nocturnal oximetry) (Velasco et al., 2002; Jackson et al., 2001; Pinto et al., 2003; Lechtzin et al., 2007b; Carratù et al., 2009), encouraging earlier use of NIPPV or the use of more sensitive tests to detect chronic alveolar hypoventilation.

According to recently published guidelines, all patients with ALS could benefit from NIPPV therapy, and a trial with this appliance should never be discouraged, although marked bulbar involvement could be associated with reduced tolerance and maybe survival (Miller

and to improve quality of life and cognitive functions in most patients (Miller et al., 2009a). At present time, NIV, usually via nasal mask with Bi-level Positive Airway Pressure (BiPAP) machines, is the most effective treatment available for ALS patients (Heiman-Patterson &

The first study that investigated the effects of NIPPV in patients with ALS dates back to 1995. In a non-randomized trial of NIPPV, Pinto and colleagues showed that survival was significantly longer in the nine patients that received NIPPV compared to the nine patients that received standard care (Pinto et al., 1995). In the following years, many cohort and retrospective studies, and a single randomized trial confirmed these results in those patients that used the ventilatory device for more than 4 hours/night (defined as tolerant patients) (Aboussouan et al., 1997, 2001; Kleopa et al., 1999; Bourke et al., 2003, 2006; Farrero et al., 2005; Gruis et al., 2005; Lo Coco et al., 2006b). In general, these studies demonstrated a median survival of 10 to 15 months in those who were able to tolerate NIPPV. It was also pointed out that NIPPV treatment could slow the rate of respiratory impairment, while severe bulbar impairment could affect NIPPV tolerance (Pinto et al., 1995; Aboussouan et al., 1997, 2001; Kleopa et al., 1999; Bourke et al., 2003, 2006; Farrero et al., 2005; Gruis et al., 2005; Lo Coco et al., 2006b). Furthermore, many recent studies showed that NIPPV therapy could improve quality of life of patients with ALS (Gelinas et al., 1998; Lyall et al., 2001a; Kaub-Wittemer et al., 2003; Bourke et al., 2003, 2006; Mustfa et al., 2006), although some suggested that the caregivers' burden could become heavier (Gelinas et al., 1998; Kaub-Wittemer et al., 2003). Finally, it has been reported that mechanical ventilation could improve cognitive

Notwithstanding the aforementioned effects on respiratory symptoms, quality of life, and survival many studies suggest that the employment of NIPPV in ALS is poor worldwide (Bourke et al., 2002; Lechtzin et al., 2004), with a need for more education of clinicians and patients regarding the benefits of mechanical ventilation earlier in the course of the disease (Bradley et al., 2001). The reasons for such low uptake of NIPPV treatment are multifactorial but are influenced by differences in the experience of physicians, its availability and cost, uncertainty of the benefits and timing for starting ventilation, and concerns that ventilatory support might prolong suffering, render home care less feasible, and lead to dependency or

Moreover, there is still debate about the optimal timing to introduce ventilation in these patients and whether early NIPPV initiation could actually lead to increased survival rates. With regard to the first aspect, as previously discussed, there are at present many different guidelines that suggest numerous exams to be performed, including upright and supine spirometry, nocturnal oximetry, blood gas analysis and MIP (Andersen et al., 2005, 2007;

Concerning to the effects of early NIPPV introduction in patients with ALS, there are some studies that reported increased compliance, quality of life and survival in those patients that received earlier treatment (mainly defined by the evidence of significant desaturations at nocturnal oximetry) (Velasco et al., 2002; Jackson et al., 2001; Pinto et al., 2003; Lechtzin et al., 2007b; Carratù et al., 2009), encouraging earlier use of NIPPV or the use of more sensitive

According to recently published guidelines, all patients with ALS could benefit from NIPPV therapy, and a trial with this appliance should never be discouraged, although marked bulbar involvement could be associated with reduced tolerance and maybe survival (Miller

function after some months of treatment (Newson-Davis et al., 2001).

ventilator entrapment (Radunović et al., 2007).

tests to detect chronic alveolar hypoventilation.

Miller et al., 2009a).

Miller, 2006).

et al., 2009a). Indeed, the increased risk of aspiration in patients with bulbar onset and problems because of difficulties in clearing secretions or obstructions, such as those related to abnormal function of the vocal cords, should be considered.

In our experience NIPPV can be well tolerated by both patients and caregivers, even in patients with bulbar involvement, especially if an intensive educational training and adaptation on NIPPV can be performed (Volanti et al., 2011). Special importance, then, should be deserved to adaptation and compliance during the first few weeks of NIPPV use, since this could be a crucial step in determining the efficacy of the treatment.

Factors predicting survival following NIPPV include advanced age, airway mucus accumulation and lower body mass index (Peysson et al., 2008; Lo Coco et al., 2006). Noncompliance with NIPPV has been related to frontotemporal dysfunction and severe bulbar involvement, whereas compliance with the treatment was associated with young age, preserved upper limb function, symptoms of orthopnea and dyspnea, use of percutaneous endoscopic gastrostomy (PEG), speech devices, and riluzole (Bourke et al., 2003, 2006; Gruis et al., 2005; Olney et al., 2005; Jackson et al., 2006). Nocturnal hypercapnea has also been recently indicated as a predictor of good compliance with subsequent NIPPV treatment (Kim et al., 2011). Oxygen supplementation should be avoided unless provided with mechanical ventilation or to treat dyspnea as a palliative, periodically monitoring CO2 levels. In fact oxygen therapy may reduce respiratory drive particularly during sleep and has been associated with CO2 retention and a less favourable outcome than ventilation (Bach et al., 1998; Gay & Edmonds, 1995).

At present, worldwide accepted guidelines propose NIPPV initiation in the presence of respiratory symptoms, and/or evidence of respiratory muscles weakness (FVC ≤ 80% of predicted or SNIP ≤ 40 cmH2O), evidence of significant nocturnal desaturation on overnight oximetry (< 90% for > 5% of the time asleep) or a morning arterial PaCO2 > 6.5 kPa (Radunović et al., 2007; Miller et al., 2009a).
