Objectives

1. Learn methods to support inspiratory and expiratory respiratory function in patients with amyotrophic lateral sclerosis.
2. Know when to consider noninvasive and invasive ventilation options.
3. Learn what factors may influence tolerance of noninvasive ventilatory support.
4. Be aware of the objective indicators of benefits of noninvasive ventilation, including survival, quality of life, and cognitive function.
5. Appreciate the ethical, financial, and medical considerations in decisionmaking concerning the use of invasive ventilatory options.

Key words

amyotrophic lateral sclerosis; attitude of health personnel; ethics; quality of life; respiration; survival

Abbreviations

ALS = amyotrophic lateral sclerosis; HMV = home mechanical ventilation; MIP = maximal inspiratory pressure; NIPPV = noninvasive positive-pressure ventilation; REM = rapid eye movement

Amyotrophic lateral sclerosis (ALS) is a progressive neurologic disorder with a prevalence of 4 to 6 per 100,000, in which death almost uniformly results from respiratory muscle involvement and associated complications. In addition, in our experience, shortness of breath can be a presenting feature of the disease in about 7% of patients. There have been several advances in the management of the respiratory impairment, including the use of noninvasive positive pressure ventilation (NIPPV),¹ methods to enhance the clearance of respiratory secretions,² use of home mechanical ventilation,³ and pharmacologic approaches such as riluzole.⁴

In this review, practical aspects of the use of NIPPV will be discussed, including factors affecting tolerance, the role of NIPPV in patients with bulbar symptoms, the types of device used, timing of the intervention, and other patterns of use. Objective measures of the efficacy of NIPPV are then reviewed, including effects on survival, quality of life, and hospitalization rates. Methods for the management of secretions are considered. The effects of home mechanical ventilation on survival and quality of life are discussed, with emphasis on advance planning and ethical perspectives from the viewpoint of the patient, the caregiver, and the physician. Finally, pharmacologic options are reviewed.

Significance

Pharmacologic and other therapeutic advances in ALS appear to have favorably altered the prognosis such that a nihilistic approach is no longer considered acceptable.⁵ However, much remains to be determined, including the exact patterns of use of NIPPV, methods to broaden tolerance of the intervention, timing of the intervention, and better pharmacologic therapies. Invasive mechanical ventilation remains an option for many patients but its implementation is dependent on a complex interplay of medical, ethical, and societal factors.

Noninvasive Ventilation

General Considerations

NIPPV is considered the treatment of choice for the management of respiratory insufficiency in patients with progressive neuromuscular diseases including ALS.⁶ It is well tolerated in some patients, and while usually offered as a bridge towards more invasive means of ventilatory support, it can also obviate the need for tracheostomy.⁷

About 50% of patients are able to tolerate NIPPV for ≥ 4 h daily,^8,9 with higher tolerance rates reported when careful attention is given to the interfaces and devices used.¹⁰ Bulbar symptoms are associated with intolerance of NIPPV⁸ and have been considered a contraindication to noninvasive ventilation when the patient is unable to clear secretions.¹¹ However, 30% of patients with moderate to severe bulbar symptoms are able to tolerate NIPPV, and tolerance of the device in this group confers a survival advantage.¹ Assisted peak cough flows of <2.7 L/s (160 L/min) combined with failure to clear secretions more accurately define individuals for whom tracheostomy may be considered.¹⁰

Once prescribed, NIPPV need not be limited to nighttime use. For instance, patients progressively increase their use of NIPPV as the disease advances, with many (33 to 65%) of the tolerant patients eventually using the device nearly continuously (>20 h/d).^3,10

Although pressure-limited ventilation may be tolerated better than volumelimited ventilation,¹ Bach¹⁰ prefers the use of volume-limited ventilation because air stacking necessary for some for the expiratory aids cannot be performed with pressure-limited devices.

Effect on Survival

Several studies show an increase in survival with NIPPV, with a median survival from initiation of the intervention of 12 to 15 months in patients who tolerate the intervention, compared with a median survival of 2 to 5 months in patients who are unable to tolerate NIPPV or are assigned to receive usual care.^1,8-10,12 In one study, >40% of tolerant patients remain alive 2 years after initiation of NIPPV,¹ and survivals of >7 years without ventilatory reserve have been reported as long as peak cough flows are preserved.¹⁰

Other Objective Measures of NIPPV Efficacy: Quality of Life, Cognitive Function, and Hospitalization Rates

Although noninvasive ventilatory support may prolong survival after the onset of respiratory insufficiency, concern was raised as to whether this prolongation of life occurs at the expense of increased disability.¹ Several subsequent studies indicate that NIPPV is associated with sustained improvements in the mastery and fatigue scores of the chronic respiratory disease questionnaire,⁸ and in the vitality score of the SF-36 scale,¹⁴ despite progression of the disease and dyspnea. Other objective measures of efficacy of NIPPV include improvements in scores on cognitive tests in a prospective study of patients with ALS,¹⁵ and a decrease in the pneumonia and hospitalization rates in a retrospective study.¹⁶

Timing of Noninvasive Ventilatory Support

Current guidelines of the American Academy of Neurology recommend counseling on the use of NIPPV when respiratory symptoms start or when FVC drops to about 50% of predicted value.¹⁷ However, there is a poor correlation between the FVC and symptoms, measurement of respiratory muscle strength, or duration of nocturnal desaturation <90%.¹⁸ Moreover, when patients with ALS are followed closely, the FVC ranges from 16 to 70% (mean, 44% predicted) at around the time of onset of hypercapnia (PaCO₂ ≥45 mm Hg) or orthopnea.¹ Supine FVC correlates highly with transdiaphragmatic pressure (R2=0.76), and a supine FVC cutoff of <75% is reported to be 100% specific and sensitive for predicting a transdiaphragmatic pressure <70 cm H₂O, raising the possibility of using supine FVC as a more sensitive marker of early respiratory compromise.¹⁹

Other measures include use of daytime blood gases, nocturnal desaturation, and respiratory muscle strength as a surrogate for nocturnal desaturation. A European consensus conference recommended daytime elevation in PaCO₂ to ≥45 mm Hg to justify initiation of noninvasive positive pressure ventilation in patients with neuromuscular disorders.²⁰ However, abnormalities in daytime gas exchange may occur late after the onset of respiratory dysfunction, particularly in rapidly progressive neurologic disorders such as ALS.

An alternative method capitalizes on the fact that sleep, and more specifically rapid eye movement (REM) sleep, may uncover respiratory disturbance events and therefore assist in the early detection of the onset of respiratory impairment in ALS. Several mechanisms underlie this observation including the normal shift of the burden of respiration to the diaphragm during REM sleep,²¹ and the predisposition of patients with bulbar ALS to hypopneas during REM sleep.^22,23 Nocturnal desaturation ≤ 88% for ≥ 5 min (consecutive) has been proposed as a simple and early marker of diaphragmatic dysfunction.²⁴ A reduction of maximal inspiratory pressure (MIP) to <60 cm H₂O has an 86% sensitivity for the presence of a nocturnal oxygen saturation nadir of ≤80%,²⁵ and was proposed as a surrogate marker of nocturnal desaturation.²⁴ Interestingly, in one study, a model incorporating MIP and supine FVC was an excellent predictor of diaphragmatic muscle strength.¹⁹

There is clearly a need to better define the optimal time to initiate intervention with NIPPV. In an ongoing trial, 80% of ALS patients randomly assigned to receive NIPPV early (ie, when there was nocturnal desaturation <90% for 1 min) had an increase in the vitality subscale of the SF-36 compared with those randomized to receive the current standard of care (ie, who received NIPPV when the FVC <50%).¹⁸

Current recommendations and reimbursement guidelines for noninvasive respiratory assistance devices in patients with documented restrictive lung disease use the following criteria:²⁴

1. An awake PaCO₂ ≥45 mm Hg at the patient’s usual fraction of inspired oxygen;
2. A sleep oximetry study demonstrating an oxygen saturation ≤88% for at least 5 continuous minutes at the patient’s usual fraction of inspired oxygen; and
3. An MIP <60 cm H₂O or a FVC ≤50% predicted.

Management of Secretions

Although inspiratory muscle weakness is primarily responsible for the development of respiratory symptoms and ventilatory failure in ALS, expiratory muscle weakness can be associated with inability to generate supramaximal flows during coughing, with consequent impairment in dynamic airway compression and compromised cough efficacy.²⁶ Authorities in the field advocate the use of expiratory aids to clearing secretions as a complement to the support of breathing,² and in retrospective studies, the use of both inspiratory and expiratory aids significantly decreased the hospitalization rates for respiratory complications of neuromuscular disease,²⁷ and improved survival.¹⁰

Expiratory aids consist of assisted cough, either manually or mechanically through an insufflator-exsufflator,²⁸ use of high-frequency oscillation techniques, training to improve maximum insufflation capacity,²⁹ and air stacking.

Air stacking enhances cough efficacy by allowing initiation of cough at higher lung volumes, and can be achieved by glossopharyngeal breathing (a technique that consist of stacking several gulps of air behind a closed glottis),³⁰ or by delivery of air via a manual resuscitator or a volume-limited ventilator.²⁹ Training in stacking of delivered volumes improves the maximum insufflation capacity in 70% of patients fulfilling the inclusion criteria, with a corresponding increase in peak cough flows from 3.7 to 4.3 L/s.29 The inclusion criteria for that latter study included a fairly preserved bulbar function so that glottic closure could allow the maximum insufflation capacity to exceed the vital capacity, a feat that 50% of ALS patients were unable to reach.²⁹

Cough efficacy can be further enhanced by an abdominal thrust timed with the cough effort² or by application of negative pressure though a mask. The mechanical insufflator-exsufflator combines elements of air stacking and cough enhancement by manual or mechanical cycling from a positive pressure that enhances lung volumes (insufflation) to a negative pressure that facilitates clearing of airway secretions (exsufflation).²⁸ One study found a progressive increase in peak expiratory flow rates from unassisted cough (1.82 L/s) to cough preceded by air stacking (3.37 L/s), cough manually assisted by chest compression (4.27 L/s), and finally to use of a mechanical insufflator-exsufflator (7.47 L/s).²⁸

Home Mechanical Ventilation: Advance Care Planning and Ethical Considerations

Survival, Costs, and Patient Characteristics

Effective ventilatory support via tracheostomy prolongs survival in ALS patients, with an 87% 1-year survival and 33% 5-year survival,³¹ although several qualityof- life indices are worse with mechanical ventilation than with NIPPV.³² Home mechanical ventilation (HMV) was reported in 1983 to be an acceptable and less expensive alternative to institutional care,³³ with a mean yearly cost of $137,000, compared with $367,000 in an institutional setting.³⁴ Quality of life was also better at home,^34,35 and in data from the Kaiser Permanente Southern California Region, quality of care was found to be similar to hospital care.³⁵ Overall, the coping mechanisms were more effective when the patient viewed his/her disease as an impairment rather than as a terminal illness.³⁶

Disparities persist in the recipients of HMV. For instance, patients with ALS receiving HMV were more likely to be male, have private insurance, and have an education beyond high school compared with patients in an institution.³⁴

Initiation and Termination of Invasive Support Options

Invasive support options should be discussed early with ALS patients,³⁷ yet in one study, only 79% of ALS patients receiving HMV were informed of the possibility of long-term mechanical ventilation before respiratory failure occurred, and although 36% had thought of it in advance, only 21% had chosen it in advance.³⁸ Not surprisingly, in 79 to 92% of patients receiving mechanical ventilation, ventilation was initiated in an emergency without a prior advance decision.^3,38 To assist in this decision, assisted peak cough flows of <2.7 L/s (160 L/min) and failure to clear secretions, as evidenced by a decrease in baseline pulse oximetry to <95%, were proposed to justify tracheostomy placement.^10,39

Patient’s Perspective

The majority of patients (>85%) elect not to have invasive ventilation, particularly when noninvasive ventilation is offered as an alternative option.^38,40 However, once mechanical ventilation has been initiated, 80 to 90% of patients are satisfied with their decision and would choose mechanical ventilation again.^34,38

Several different and seemingly contradictory views are expressed in studies of patients dependent on invasive means of mechanical ventilation, perhaps because many do not realize the full impact of their illness until some time after ventilatory support has been initiated.³⁶ For instance, 63% of patients already using HMV report that they would not have wanted their physicians to discuss that option ahead of time because they would not have wanted to know.³⁸ Others report that when patients did not have the opportunity to discuss that option before it became necessary, they express discontent and anger about the outcome.³⁷ Moreover, in another report, 70% of patients preferred to participate in decisions about their own medical care,⁴¹ yet in another study, patients with ALS felt that they should be the only ones making a decision about mechanical ventilatory support.⁴²

The patient’s opinion on end-of-life issues may change with time and should be periodically reassessed. For instance, at an initial interview, 74% of ALS patients said they would like to make their own medical decisions, compared with 66% at a follow-up interview; 35% of patients with an opinion concerning cardiopulmonary resuscitation (either for or against) would change their opinion on a follow-up interview 6 months later.⁴¹

Finally, 76% of patients receiving long-term mechanical ventilation report that they would want the intervention discontinued under certain circumstances.³⁴ Once the goals of withdrawing life-sustaining intervention have been defined with the patient and his/her family, withdrawal of mechanical ventilation can be initiated while taking care of ensuring the patient’s comfort.⁴³

Caretaker’s Perspective

While most caregivers are supportive of the patient’s choice for HMV, many studies describe a discrepancy between the attitude of caregivers and that of patient. For instance, whereas 90% of patients with ALS receiving HMV would choose this option again if they hypothetically had to make that decision again, only 50% of caregivers would choose to do so.³⁸ Patients tend to overestimate the quality of life of their caregivers, whereas caregivers tend to underestimate the patient’s quality of life to a greater degree.⁴⁰ Another consideration is that even when different family members initially decide to share the responsibility for the patient’s care, one person often ends up with most of those responsibilities³⁶; in 90% of cases that caregiver is a woman, most often the spouse.³⁸

Physician’s Perspective

The physician’s perspective and opinion on home ventilation clearly influences the decision and final outcome of a patient who faces treatment options for respiratory failure.^38,44 For instance, in a survey of Muscular Dystrophy Association directors, the director’s assessment of quality of life and satisfaction with life while receiving mechanical ventilation correlated with the likelihood of discussions and recommendations on its use to prolong life.⁴⁵ Similarly, in a survey of five different ALS treatment centers, the proportion of patients receiving HMV depended on whether the physicians of the center would consider HMV for themselves and whether they presented that option negatively or in a neutral fashion.³⁸ Of interest, 24% of physicians surveyed reported that they would delay a discussion on HMV until respiratory failure occurred.³⁸

Medications and Preventive Measures

Riluzole

In an evidence-based review of several randomized controlled trials, riluzole, at a dose of 100 mg daily, was found to prolong tracheostomy-free survival by about 2 months.⁴ There is some doubt as to whether it is effective in the elderly⁴⁶ and in advanced disease.⁴⁷ Of interest, riluzole appears to be of greater benefit in patients with bulbar-onset ALS.^47,48

Role of Theophylline

Theophylline has been found to have beneficial effects on the contractility of the diaphragm, although larger studies have had mixed results.⁴⁹ In patients with ALS, one study found that theophylline increased negative inspiratory pressure, vital capacity, and peak inspiratory flow rate after breathing through a resistive load.⁵⁰ A significant concern remains as to whether any therapeutic benefit would come at the expense of toxicity, given the narrow therapeutic window of this agent.⁴⁹

Oxygen Therapy

In a retrospective review of patients with neuromuscular disease, there was a mean increase in PaCO₂ by 28 mm Hg after initiation of low-flow oxygen.⁵¹ Additionally, in one large study of patients with neuromuscular disease, there was a higher rate of pneumonias and hospitalizations in patients receiving oxygen therapy compared with that seen in untreated patients or in those using other modalities of ventilatory support.¹⁶ While initiation of nocturnal assisted ventilation allowed the use of daytime oxygen supplementation with less severe hypercapnia,⁵¹ some authors note that oxygen supplementation results in the inability to use oximetry to determine the efficacy of alveolar ventilation and airway clearance.¹⁶

Pharmacologic Approaches to the Treatment of Sialorrhea

Although saliva production is decreased in patients with ALS, poor handling of secretions in the presence of bulbar symptoms results in significant discomfort for the patient.¹⁷ Pharmacologic options for its treatment include glycopyrrolate (1 to 2 mg q4h prn), amitriptyline (10 to 50 mg q4h prn), and transdermal scopolamine (1.5-mg patch every 3 days).¹⁷ Sialorrhea should be distinguished from excessive and thick mucus production, which requires different treatment options.¹⁷

Prevention of Complications

Other important measures are preventive in nature and consist of administration of pneumococcal vaccination and yearly influenza vaccination unless there is a contraindication. Deep venous thrombosis prophylaxis is also a consideration in individuals with lower-extremity weakness. Careful and periodic assessment of the integrity of swallowing should be performed and a percutaneous endoscopic gastrostomy should be considered when appropriate.¹⁷ Percutaneous endoscopic gastrostomy tubes have been shown to improve quality of life, weight, and survival,⁵² and should be inserted preferably before the FVC drops to 50% of predicted,¹⁷ although NIPPV can be used during the procedure in patients with severe respiratory dysfunction who may not otherwise tolerate the intervention.⁵³

Conclusions

Death from ALS predominantly occurs as a result of respiratory failure. Recent pharmacologic therapies, along with inspiratory and expiratory support of respiration, have had a favorable impact on survival, quality of life, cognitive function, and hospitalization rates to the extent that a nihilistic approach is no longer acceptable.⁵

The timing of NIPPV and exact selection of patients for NIPPV vs invasive ventilatory support depends on a complex interplay of medical, ethical, and societal factors. While the standard of care recommends initiation of NIPPV at a vital capacity <50%, ongoing randomized trials reveal that initiation at the onset of nocturnal desaturation is associated with an increase in vitality. Several studies show that patients with bulbar symptoms may still benefit from noninvasive ventilation if they are able to tolerate the intervention, although peak cough flows <2.7 L/s more accurately identify patients who may require tracheostomy.

Concerning HMV, it is important to recognize that the attitudes of patients and their caregivers towards treatment options should be addressed early in the course of the disease, separately for the patient and caregiver, and reassessed periodically. Advance planning concerning such end-of-life issues should be encouraged and lead to advance directives.⁵⁴ Although decision making is based on the patient’s autonomy, conflicts can frequently arise between the health-care expenditures system and the patient’s autonomy,⁵⁵ as is evident from the disparities in income and insurance coverage that exist between patients undergoing HMV and those who receive their mechanical ventilation in an institutional setting.

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