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

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 problematic, leading to further pulmonary complications.

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

Assessment and Management of

(Goncalves & Bach, 2005).

2004).

al., 2006).

2009).

Thoracic Society, 2005)*.*

Respiratory Dysfunction in Patients with Amyotrophic Lateral Sclerosis 585

management of patients with ALS (Sancho et al., 2004) and to be effective in prolonging non-invasive respiratory aids delaying the need for tracheostomy (Bach, 2002). However, this device seems to be ineffective in patients with severe bulbar dysfunction (Bach, 2002; Sancho et al., 2004), perhaps because the application of the exsufflation cycle of MI-E for those patients with weakness of the genioglossus activity due to bulbar dysfunction might produce a dynamic, total, or partial collapse of the upper airway (Sancho et al.,

It is useful to remember that for patients whose vital capacities are less than normal, manually assisted coughing is not optimally effective unless preceded by a maximal lung insufflation, and MI-E is not optimal unless an abdominal trust is applied during the exsufflation (Goncalves & Bach, 2005). Then abdominal trusts and MI-E should be combined together for effective prevention of lower respiratory tract infection and respiratory insufficiency. Failure to correctly administer physical medicine aids continues to make respiratory failure inevitable for the great majority of people with neuromuscular diseases

Finally, high-frequency chest-wall oscillation (HFCWO), another airway-clearance technique, has been recently evaluated in a 12-week randomized, controlled trial on 46 patients with ALS (Lange et al., 2006). HFCWO is a technique that, through generation of high flow in the small airways, is thought to mobilize secretions from the distal airways to the larger airways, from where they can be more easily removed. It has been reported that HFCWO is well tolerated, considered to be helpful by a majority of patients, and decreases symptoms of breathlessness, suggesting that the intervention was useful in the clearance of airway secretions in patients with ALS (Lange et al., 2006). Another study, however, failed to show any benefit in loss of lung function or mortality in 9 patients with ALS (Chaisson et

A part from sustaining respiration with mechanical devices, special consideration should be given to prevention of aspiration and development of pneumonia (Radunović et al., 2007; Miller et al, 2009 a,b). In this regard, it is of fundamental importance the reduction of the amount of salivary secretions through the use of several medications (such as amitriptyline and botulinum toxin injections), devoting adequate amount of time in teaching proper swallowing technique, and maintaining hydration. It is also useful to provide a portable mechanical home suction device. In addition, when dysphagia worsens, placement of a PEG tube should be the preferred option, especially when the respiratory function is not too much compromised. Smoking cessation advice should be offered to all patients who are current smokers. Influenza and pneumococcal immunization should be encouraged during the progression of the disease, although ALS has not been included in specific risk-group recommendations available so far. In case of acute pneumonia, adequacy and length of treatment, proper dosages and intervals of administration, and reduction of delay of initial antibiotic treatment are all important issues (American Thoracic Society, 2005; Lim et al.,

Antibiotic prophylaxis strategies are especially useful to prevent ventilator-associated pneumonia, whereas passive humidifiers or heat–moisture exchangers decrease ventilator circuit colonization, but have not consistently reduced the incidence of ventilator-associated pneumonia, and thus they cannot be regarded as a pneumonia prevention tool (American

337 L/min had a significantly greater chance of being alive at 18 months (Chaudri et al., 2002).

Methods of treatment include breathing exercises, postural drainage, exercise regimens and the use of assisted cough techniques (Lo Coco et al., 2008).

Medications with mucolytics like guaifenesin or N-acetylcysteine, a -receptor antagonist (such as metoprolol and propanolol), nebulized saline, or an anticholinergic bronchodilator such as ipratropium are widely used, although no controlled studies exist in ALS (Miller et al., 2009a).

The benefit of breathing exercises is difficult to evaluate but their main aims can be summarized as: to promote a normal breathing pattern; to teach controlled breathing for use during attacks of dyspnoea; in conjunction with forced expiration technique and postural drainage to assist the removal of secretions; and to maintain the mobility of the chest wall. Patients must be carefully instructed by a physiotherapist and should practise these exercises regularly.

Patients who have excess secretions in the bronchial tree or difficulties in secretions removal may benefit from postural drainage. Postural drainage can be defined as the placement of a patient in various positions so that, with the aid of gravity, secretions may drain from the peripheral to the more central areas of the lung and thus become more easily expectorated. The positions to be used and also the length of time spent in each position must be determined for each patient by a skilled physiotherapist. Clearance of bronchial secretions by postural drainage may be further assisted by the use of deep breathing, percussion and chest vibration, which may be combined with compression of the chest wall and also with the use of the forced expiration technique. However, patients with limited mobility and muscle weakness have difficulty with postural drainage and generally do not benefit from chest physical therapy (Kirilloff et al., 1985). Moreover, intensive cycles of physiotherapy may be exhausting for many patients, particularly those with advanced disease, and may cause arterial desaturation.

Interestingly, a recent double-blind, randomized-controlled trial showed that inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS (Cheah et al., 2009).

Among non-invasive expiratory aids, manually assisted coughing techniques, such as anterior chest compression and abdominal trust, have been shown to be effective in facilitating the elimination of airway secretions in patients with neuromuscular diseases (Massery & Frownfelter, 1990; Bach, 1993a). Nevertheless, manually assisted coughing is labour intensive and often difficult for non-professional caregivers, both during outpatient and in-hospital management, and it depends on precise care provider-patient coordination (Vianello et al., 2005).

The mechanical in-exsufflator (MI-E) is a device that assists patients in clearing bronchial secretions. It consists of a two-stage axial compressor that provides positive pressure (that causes a deep insufflation), thereby generating a forced expiration in which high expiratory flow rates and a high expiratory pressure gradient are generated between the mouth and the alveoli. It is usually applied via a facemask. The use of MI-E has been described to be simple and safe enough for application by non-professional caregivers (Bach, 1993a, 1994), and has been proposed as a complement to manually assisted coughing in the prevention of pulmonary morbidity in neuromuscular patients (Tzeng & Bach, 2000; Bach et al., 1993b). MI-E has also been shown to be helpful in the

337 L/min had a significantly greater chance of being alive at 18 months (Chaudri et al.,

Methods of treatment include breathing exercises, postural drainage, exercise regimens and

Medications with mucolytics like guaifenesin or N-acetylcysteine, a -receptor antagonist (such as metoprolol and propanolol), nebulized saline, or an anticholinergic bronchodilator such as ipratropium are widely used, although no controlled studies exist in ALS (Miller et

The benefit of breathing exercises is difficult to evaluate but their main aims can be summarized as: to promote a normal breathing pattern; to teach controlled breathing for use during attacks of dyspnoea; in conjunction with forced expiration technique and postural drainage to assist the removal of secretions; and to maintain the mobility of the chest wall. Patients must be carefully instructed by a physiotherapist and should practise these

Patients who have excess secretions in the bronchial tree or difficulties in secretions removal may benefit from postural drainage. Postural drainage can be defined as the placement of a patient in various positions so that, with the aid of gravity, secretions may drain from the peripheral to the more central areas of the lung and thus become more easily expectorated. The positions to be used and also the length of time spent in each position must be determined for each patient by a skilled physiotherapist. Clearance of bronchial secretions by postural drainage may be further assisted by the use of deep breathing, percussion and chest vibration, which may be combined with compression of the chest wall and also with the use of the forced expiration technique. However, patients with limited mobility and muscle weakness have difficulty with postural drainage and generally do not benefit from chest physical therapy (Kirilloff et al., 1985). Moreover, intensive cycles of physiotherapy may be exhausting for many patients, particularly those with advanced disease, and may

Interestingly, a recent double-blind, randomized-controlled trial showed that inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in

Among non-invasive expiratory aids, manually assisted coughing techniques, such as anterior chest compression and abdominal trust, have been shown to be effective in facilitating the elimination of airway secretions in patients with neuromuscular diseases (Massery & Frownfelter, 1990; Bach, 1993a). Nevertheless, manually assisted coughing is labour intensive and often difficult for non-professional caregivers, both during outpatient and in-hospital management, and it depends on precise care provider-patient coordination

The mechanical in-exsufflator (MI-E) is a device that assists patients in clearing bronchial secretions. It consists of a two-stage axial compressor that provides positive pressure (that causes a deep insufflation), thereby generating a forced expiration in which high expiratory flow rates and a high expiratory pressure gradient are generated between the mouth and the alveoli. It is usually applied via a facemask. The use of MI-E has been described to be simple and safe enough for application by non-professional caregivers (Bach, 1993a, 1994), and has been proposed as a complement to manually assisted coughing in the prevention of pulmonary morbidity in neuromuscular patients (Tzeng & Bach, 2000; Bach et al., 1993b). MI-E has also been shown to be helpful in the

respiratory function in patients with ALS (Cheah et al., 2009).

the use of assisted cough techniques (Lo Coco et al., 2008).

2002).

al., 2009a).

exercises regularly.

cause arterial desaturation.

(Vianello et al., 2005).

management of patients with ALS (Sancho et al., 2004) and to be effective in prolonging non-invasive respiratory aids delaying the need for tracheostomy (Bach, 2002). However, this device seems to be ineffective in patients with severe bulbar dysfunction (Bach, 2002; Sancho et al., 2004), perhaps because the application of the exsufflation cycle of MI-E for those patients with weakness of the genioglossus activity due to bulbar dysfunction might produce a dynamic, total, or partial collapse of the upper airway (Sancho et al., 2004).

It is useful to remember that for patients whose vital capacities are less than normal, manually assisted coughing is not optimally effective unless preceded by a maximal lung insufflation, and MI-E is not optimal unless an abdominal trust is applied during the exsufflation (Goncalves & Bach, 2005). Then abdominal trusts and MI-E should be combined together for effective prevention of lower respiratory tract infection and respiratory insufficiency. Failure to correctly administer physical medicine aids continues to make respiratory failure inevitable for the great majority of people with neuromuscular diseases (Goncalves & Bach, 2005).

Finally, high-frequency chest-wall oscillation (HFCWO), another airway-clearance technique, has been recently evaluated in a 12-week randomized, controlled trial on 46 patients with ALS (Lange et al., 2006). HFCWO is a technique that, through generation of high flow in the small airways, is thought to mobilize secretions from the distal airways to the larger airways, from where they can be more easily removed. It has been reported that HFCWO is well tolerated, considered to be helpful by a majority of patients, and decreases symptoms of breathlessness, suggesting that the intervention was useful in the clearance of airway secretions in patients with ALS (Lange et al., 2006). Another study, however, failed to show any benefit in loss of lung function or mortality in 9 patients with ALS (Chaisson et al., 2006).

A part from sustaining respiration with mechanical devices, special consideration should be given to prevention of aspiration and development of pneumonia (Radunović et al., 2007; Miller et al, 2009 a,b). In this regard, it is of fundamental importance the reduction of the amount of salivary secretions through the use of several medications (such as amitriptyline and botulinum toxin injections), devoting adequate amount of time in teaching proper swallowing technique, and maintaining hydration. It is also useful to provide a portable mechanical home suction device. In addition, when dysphagia worsens, placement of a PEG tube should be the preferred option, especially when the respiratory function is not too much compromised. Smoking cessation advice should be offered to all patients who are current smokers. Influenza and pneumococcal immunization should be encouraged during the progression of the disease, although ALS has not been included in specific risk-group recommendations available so far. In case of acute pneumonia, adequacy and length of treatment, proper dosages and intervals of administration, and reduction of delay of initial antibiotic treatment are all important issues (American Thoracic Society, 2005; Lim et al., 2009).

Antibiotic prophylaxis strategies are especially useful to prevent ventilator-associated pneumonia, whereas passive humidifiers or heat–moisture exchangers decrease ventilator circuit colonization, but have not consistently reduced the incidence of ventilator-associated pneumonia, and thus they cannot be regarded as a pneumonia prevention tool (American Thoracic Society, 2005)*.*

Assessment and Management of

Coco et al., 2007).

al., 2007).

**6. Conclusion** 

ventilation in ALS (Miller et al., 2009b).

impairment (Lo Coco et al., 2008).

useful for this purpose.

Respiratory Dysfunction in Patients with Amyotrophic Lateral Sclerosis 587

known in advance of a respiratory crisis (Silverstein et al., 1991; Andersen et al., 2005, 2007). Indeed, once intubated, patients can rarely get free from the ventilator. These preferences should also be reviewed periodically during the course of the disease, since patients' desires concerning life-sustaining interventions might change with disease progression. Ideally, emergency intubation and tracheostomy should be avoided (Andersen et al., 2005, 2007), but this is a much debated question, since there is not universal consent from public authorities. As a result, the percentage of patients that had been tracheotomized without informed consent is very high across studies (Moss et al., 1993, 1996; Cazzoli & Oppenheimer, 1996; Lo

Symptomatic treatment of severe dyspnea includes use of opioids (morphine) alone or in combination with benzodiazepines (such as lorazepam, diazepam or midazolam), if significant anxiety is present (Voltz & Borasio, 1997; Miller et al., 1999; Andersen et al., 2007; Clemens et al., 2008). Relief of dyspnea using opioids was rated as good by 81% of hospice patients with ALS. (O'Brien et al., 1992). Dose titration against clinical symptoms is recommended and rarely results in life-threatening respiratory depression. Anxiety of choking correlated highly significantly with the intensity of dyspnea (Clemens et al., 2008). Terminal relentlessness and confusion secondary to hypecapnia could be relieved by administration of neuroleptic drugs (Voltz & Borasio, 1997; Miller et al., 1999; Andersen et

There are some case series offering practical advice for withdrawing both invasive and noninvasive ventilation, including frequent and repeated discussions and counseling with the patient and his family, assessment for discomfort, such as dyspnea, agitation, or anxiety, and symptom management during the withdrawal process with morphine and benzodiazepines (such as diazepam) (Borasio &, Voltz, 1998; Ankrom et al., 2001; O'Mahony et al., 2003). However, there are no controlled studies specifically examining withdrawal of

Recent publications provided important contributions to many aspects of respiratory care for patients with ALS, such as non-invasive ventilation and assisted cough. There is a need for regular assessment and follow up of respiratory function, and investigations should include daytime assessment of respiratory function (including FVC and SNIP) as well as sleep studies in order to ensure early recognition of patients with respiratory muscle

At present time the only approved pharmacological treatment for ALS is riluzole, which extends survival by about 2 months (Miller et al., 2007). On the other hand, NIPPV treatment allows survival for longer periods of time, improves quality of life, and may probably alter the disease course. As a consequence, NIPPV should be considered a major treatment option in patients with chronic hypoventilation or in whom respiratory impairment has become evident during sleep despite normal diurnal respiratory function. Every effort, then, should be made to improve NIPPV implementation in the management of patients with ALS worldwide, since it is still underutilized. The degree of hypoventilation that should prompt introduction of NIPPV must be defined further, even if there is a general tendency toward earlier intervention. Nocturnal hypoventilation could be particularly

### **5. Invasive mechanical ventilation**

ALS is a relentless pathology that causes progressive muscle dysfunction. Therefore respiratory capacity eventually fails, despite NIPPV treatment. Indeed, at first, NIPPV is generally used for intermittent nocturnal support to alleviate symptoms of nocturnal hypoventilation, although as respiratory function worsens, patients tend to require increasing daytime support and eventually continuous support. When all the respiratory aids fail to maintain adequate blood oxygen saturation, the only intervention that allows survival of these patients is invasive mechanical ventilation through a tracheostomy tube. Treatment failure seems not to be dependent on lung or respiratory muscle function but on bulbar dysfunction (Bach et al., 2004).

When placed on invasive ventilation patients are supported from a respiratory point of view; however, the loss of motor neurons goes on progressively, leading to complete paralysis and muscular atrophy. Some patients may eventually reach a "locked in" state in which they cannot communicate at all, because there is also total paralysis of the extraocular muscles. When connected to tracheostomy tubes patients may survive for many years, with respiratory tract infections the most frequent cause of death (Bradley et al., 2002; Hayashi & Oppenheimer, 2003; Lo Coco et al., 2007; Marchese et al., 2008; Vianello et al., 2011). Median survival time usually ranges from 2 to 4 years. Interestingly, the amyotrophic lateral sclerosis functional rating scale (ALSFRS), a disease-specific rating scale that assesses functional impairment, has been shown to predict both length of hospital stay as a result of acute respiratory failure and survival after initiation of invasive ventilation in these patients (Lo Coco et al., 2007).

Notwithstanding its effect on survival, only a minority of patients with ALS receive invasive mechanical ventilation, at least in the western Countries (Moss et al., 1993; Miller et al., 2000; Neudert et al., 2001). On the contrary, in Japan the frequency of invasive ventilation is considerably higher. Many patients are treated in emergency without advance planning, because of a respiratory crisis, whereas the number of patients that electively choose this treatment is low (Moss et al., 1993, 1996; Cazzoli & Oppenheimer, 1996; Lo Coco et al., 2007). Socio-economic reasons may be one of the possible explanations for the low prevalence of invasive ventilation in ALS, given the relatively high costs of this treatment. Moreover there is a need for 24-hour-caregiving, which could be perceived by caregivers and relatives as extremely burdensome. A recent study suggested that the choice of invasive ventilation was consistent with a sustained sense that life was worth living in any way possible, at least for some time and within certain boundaries, although it may involve unrealistic expectations of cure by some (Rabkin et al., 2006). Moreover, the attitudes of the treating physician have also a great influence (Moss et al., 1993), and there is concern that tracheostomy will prolong life beyond the point that the patient can communicate or interact with others.

Despite these many doubts and concerns, the majority of patients that underwent invasive ventilation were positive about their choice (Moss et al., 1993), reporting a satisfying quality of life (Cazzoli & Oppenheimer, 1996; Kaub-Wittemer et al., 2003), and indicating that they would repeat the choice again in the same situation. Caregivers were more frequently burdened and distressed by this intervention and they frequently witnessed a marked reduction of social life activities (Cazzoli & Oppenheimer, 1996; Gelinas et al., 1998; Kaub-Wittemer et al., 2003; Rabkin et al., 2006).

It is good practice that patients together with their families discuss end-of-life issues and preferences with the physician, so that advance directives and patient's wishes are well known in advance of a respiratory crisis (Silverstein et al., 1991; Andersen et al., 2005, 2007). Indeed, once intubated, patients can rarely get free from the ventilator. These preferences should also be reviewed periodically during the course of the disease, since patients' desires concerning life-sustaining interventions might change with disease progression. Ideally, emergency intubation and tracheostomy should be avoided (Andersen et al., 2005, 2007), but this is a much debated question, since there is not universal consent from public authorities. As a result, the percentage of patients that had been tracheotomized without informed consent is very high across studies (Moss et al., 1993, 1996; Cazzoli & Oppenheimer, 1996; Lo Coco et al., 2007).

Symptomatic treatment of severe dyspnea includes use of opioids (morphine) alone or in combination with benzodiazepines (such as lorazepam, diazepam or midazolam), if significant anxiety is present (Voltz & Borasio, 1997; Miller et al., 1999; Andersen et al., 2007; Clemens et al., 2008). Relief of dyspnea using opioids was rated as good by 81% of hospice patients with ALS. (O'Brien et al., 1992). Dose titration against clinical symptoms is recommended and rarely results in life-threatening respiratory depression. Anxiety of choking correlated highly significantly with the intensity of dyspnea (Clemens et al., 2008).

Terminal relentlessness and confusion secondary to hypecapnia could be relieved by administration of neuroleptic drugs (Voltz & Borasio, 1997; Miller et al., 1999; Andersen et al., 2007).

There are some case series offering practical advice for withdrawing both invasive and noninvasive ventilation, including frequent and repeated discussions and counseling with the patient and his family, assessment for discomfort, such as dyspnea, agitation, or anxiety, and symptom management during the withdrawal process with morphine and benzodiazepines (such as diazepam) (Borasio &, Voltz, 1998; Ankrom et al., 2001; O'Mahony et al., 2003). However, there are no controlled studies specifically examining withdrawal of ventilation in ALS (Miller et al., 2009b).
