The Management of Respiratory Insufficiency in Patients With ALS at or Near the End of Life

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing progressive paralysis and eventual death, usually from respiratory failure. Treatment for ALS is focused primarily on optimal symptom management because there is no known cure. Respiratory symptoms that occur are related to the disease process and can be very distressing for patients and their loved ones. Recommendations on the management of respiratory insufficiency are provided to help guide clinicians caring for patients with ALS.

Introduction

Figure

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by progressive muscle weakness eventually leading to paralysis and death. The onset typically occurs in late middle age, with men slightly more affected than women (^{Wood-Allum & Shaw, 2010}). The majority of cases of ALS have no known cause; about 10% of ALS cases are linked to a familial trait (^{Ferguson & Elman, 2007}). Treatment is primarily focused on optimal symptom management and palliative care as the etiology and pathophysiology remain unknown, and there is no cure for the disease to date (^{Elman et al., 2007; Wood-Allum & Shaw, 2010}).

There are many theories about causative factors of ALS, such as toxic accumulations of glutamate, oxidative stress, and genetic links that are currently being researched; the evidence suggests it is a polyfactorial, multigenic disease (^{Corcia & Meininger, 2008; Valente & Karp, 2007}). The theory that glutamate toxicity results in neuronal cell death led to the development of riluzole, the only medication approved for treatment (^{Ferguson & Elman, 2007}). Although the drug is very expensive—costing about $10,000 per year—this medication slows the disease's progression and can extend life by at least 2 to 3 months (^{Ferguson & Elman, 2007; Miller et al., 2009}).

The typical disease course varies between patients, but the most common presentation is a unilateral weakness involving one body segment that progressively becomes worse over time and spreads to other areas of the body (^{Ferguson & Elman, 2007}). Approximately one-third of ALS patients present with symptoms of difficulty speaking or swallowing known as bulbar dysfunction (^{Ferguson & Elman, 2007}). Signs and symptoms of ALS that indicate bulbar weakness include dysarthria, dysphagia, tongue atrophy or weakness, drooling, and muscle twitches called fasciculations (^{Ferguson & Elman, 2007}). Usually bowel and bladder control and eye movements are spared by the disease, but not always (^{Mitsumoto & Rabkin, 2007}).

There is no definitive diagnostic test for ALS; diagnosis is based on the loss of both upper and lower motor neurons in multiple body segments (^{Ferguson & Elman, 2007}). The diagnostic process can be a difficult and lengthy process as patients undergo multiple diagnostic tests to rule out other disease processes (^{Ferguson & Elman, 2007}). By the time most patients are definitively diagnosed, they are often already in an advanced stage of the disease (^{Wood-Allum & Shaw, 2010}). Life expectancy is typically 3–5 years from the onset of symptoms (^{Elman et al., 2007}).

Palliative Care Approaches for ALS Patients

Due to the progressive nature of ALS, early palliative care is an essential component in the treatment plan, and should begin as soon as the diagnosis of ALS is confirmed (^{Elman et al., 2007}). Palliative care aims to prevent and alleviate suffering while improving quality of life for patients and their families (^{Morrison & Morrison, 2006}). It is a holistic approach to care, tending to the physical, spiritual, and psychosocial needs of patients who are living with advanced disease (^{McCluskey, 2007}). As ALS progresses into the terminal phase, patients then qualify for hospice care.

In the United States, hospice care is a formal and reimbursed program of palliative care that always involves an interdisciplinary team, including a physician, nurse, hospice aide, social worker, chaplain, volunteers, and at times other members of the healthcare team such as physical, occupational, speech, and respiratory therapists. Alternative therapies such as music therapy, art therapy, and massage are provided to patients. In addition, hospice provides medical equipment, supplies, and medications to manage symptoms. To qualify for hospice care, physician certification verifying an expected prognosis of 6 months or less if the disease runs its typical course is necessary. The present Medicare criteria for hospice care specific to ALS patients are listed in Supplemental Digital Content 1, https://links.lww.com/HHN/A7. According to the Medicare criteria, patients must display a rapid progression of the ALS disease process and have significant nutritional or respiratory impairment meeting all of the characteristics listed to be in the terminal stage of the disease process (^{McCluskey & Houseman, 2004}). Medicare's criteria are viewed as being too stringent by many clinicians who work with ALS patients (^{McCluskey & Houseman, 2004; Mitsumoto et al., 2005}). It is recommended that readers check with their fiscal intermediary Medicare administrator contractors for any ALS-specific policies.

Because the majority of patients with ALS die from respiratory failure, it is important for clinicians working with these patients to effectively manage their respiratory symptoms as the disease progresses. The following literature review provides evidence-based recommendations for the management of respiratory insufficiency experienced by patients with ALS at and near the end-of-life.

ALS: Management of Respiratory Insufficiency

Overview of Respiratory Insufficiency in Patients with ALS

Because the majority of patients with ALS die from respiratory failure, interventions to help manage respiratory insufficiency and improve control of symptoms related to breathing are crucial (^{Miller et al., 2009}). Respiratory insufficiency in ALS is caused by the disease process itself; death of the nerve cells that innervate the respiratory muscles leads to weakness of the muscles of inspiration, expiration, the accessory muscles, and the upper airway muscles (^{Gregory, 2007}). Weakness of the diaphragm, the most important muscle for inspiration, often leads to nocturnal hypoventilation in part because the supine position during sleep further negatively impacts a weakened diaphragm (^{Gregory, 2007}). Patients with ALS often may report the following initial symptoms: morning headaches, orthopnea, daytime sleepiness, and poor sleep (^{Gregory, 2007}). As the disease progresses reports of a weak cough, difficulty blowing the nose and clearing secretions, and dyspnea at rest occur because of advanced respiratory musculature weakness (^{Elman et al., 2007; Gregory, 2007}). Signs of respiratory insufficiency that may be seen on clinical exam may include tachypnea and the use of accessory muscles or paradoxical breathing (^{Elman et al., 2007}).

Diagnostic Testing to Evaluate Respiratory Muscle Strength in Patients With ALS

There are a number of tests available to measure inspiratory respiratory muscle function; the forced vital capacity (FVC) is the most commonly used (^{Heffernan et al., 2006}). Using a spirometer, patients are instructed to take the deepest breath possible and then exhale forcefully as long as possible and the volume of air exhaled is measured (^{Gregory, 2007}). Patients with ALS have measurements taken both sitting upright and lying supine (^{Andersen et al., 2007; Gregory, 2007}). An abnormal FVC value is anything less than 80% of predicted (^{Gregory, 2007}). Another method used is the maximal inspiratory pressure (MIP). The patient is instructed to inhale against an occluded airway and the pressure is then recorded by a manometer (^{Gregory, 2007}). An MIP value of less than -60 cm H₂O implies inspiratory muscle weakness (^{Gregory, 2007}). For a quick reference for diagnostic tools, see Table 1.

Table 1: Quick Reference Tool

The MIP value may be difficult to interpret for ALS patients who have severe oral muscle weakness because their value may be low simply due to difficulty performing the test (^{Gregory, 2007}). The sniff nasal pressure (SNP) is a newer method to measure inspiratory respiratory muscle strength that is easier for patients with oral muscle weakness to perform (^{Gregory, 2007}). A pressure transducer is inserted into one nostril and the patient is asked to sniff (^{Gregory, 2007}). The pressure obtained from sniffing correlates well with the transdiaphragmatic pressures and has shown to be a more reliable indicator of respiratory function in patients with ALS (^{Gregory, 2007; Miller et al., 2009}). An SNP value of less than 65 cm H₂O is abnormal indicating diaphragm weakness (Corcia & Meininger, 2007). An SNP result less than 40 cm H₂O is a predictor of nocturnal hypoxemia and mortality in ALS patients (^{Gregory, 2007}).

Two tests available to measure expiratory muscle function, are the maximal expiratory pressure (P_Emax) and the peak cough expiratory flow (PCEF) (^{Gregory, 2007}). The P_Emax is measured by a pressure transducer while the patient exhales against an occluded airway (^{Gregory, 2007}). The PCEF is measured by having a patient cough into a peak flow meter, and helps to indicate a patient's ability to cough and clear secretions (^{Gregory, 2007}). Similar to the MIP, patients with severe bulbar dysfunction may have low readings on the P_Emax related to difficulty performing the test (^{Gregory, 2007}). When abnormalities in expiratory respiratory muscle function are detected such as a PCEF below 270 L/min, cough assist manual techniques and devices are recommended to promote respiratory secretion clearance and prevent pulmonary infections (^{Gregory, 2007; Phukan & Hardiman, 2009}). These include the use of manual abdominal thrusts and a mechanical insufflator-exsufflator machine. It delivers pressurized gas into the lungs to assist with inflation through a tube inserted in the mouth, and then the machine exerts negative pressure to assist with cough and removal of pulmonary secretions when activated (^{Gregory, 2007; Phukan & Hardiman, 2009}). High-frequency chest wall oscillation through a vest may also be used to mobilize and assist with pulmonary secretion clearance, although the American Academy of Neurology reports there is not strong evidence to support or refute this treatment for ALS patients (^{Miller et al., 2009}).

Additional tests to evaluate respiratory function in patients with ALS include morning arterial blood gas (ABG) sampling, pulse oximetry, blood bicarbonate level, and sleep quality through nocturnal oximetry and polysomnography (PSG; Corcia & Meininger, 2007). Abnormal results indicating respiratory dysfunction include the following: an ABG sampling with the pCO₂ greater than 45 mm Hg; blood bicarbonate level greater than 30 mmol/L; oxygen saturation levels less than 90% for more than 5 minutes of recording time, or less than 88% for 5 consecutive minutes (Corcia & Meininger, 2007). PSG requires patients with ALS to sleep overnight in a laboratory, which may be difficult and impractical for some patients with ALS, but it does provide important information about sleep fragmentation and hypoventilation for patients that are able to complete the test (^{Gregory, 2007}).

It is important to note there is not any one test to predict hypercapnia that is proven more reliable than others (^{Heffernan et al., 2006}). A combination of tests tailored to the patient's needs is most appropriate to detect early respiratory insufficiency (^{Heffernan et al., 2006}). Respiratory function should be evaluated in patients with ALS with the use of both laboratory tests and a clinical evaluation at a minimum of every 3 months or earlier with any change in symptoms (Corcia & Meininger, 2007; ^{Gregory, 2007}). When patients with ALS have abnormal laboratory results through pulmonary function testing or experience symptoms of respiratory dysfunction, the American Academy of Neurology recommends clinicians to initiate noninvasive ventilation (NIV) as a first line of treatment for respiratory insufficiency (^{Miller et al., 2009}).

Treatment Options for ALS Patients With Evidence of Respiratory Insufficiency

Treatment options for patients with ALS vary with some being more aggressive than others. When there is evidence of respiratory insufficiency, NIV is a recommended treatment strategy (^{Andersen et al., 2007; Miller et al., 2009; Mitsumoto et al., 2005}). Other treatments related to respiratory function recommended for patients with ALS include cough assist devices (see Figure 1), suction machinery, flu and pneumococcal vaccines, and aggressive treatment of pulmonary infections (^{Gregory, 2007}). Regardless of whether or not a patient uses NIV, discussions about long-term mechanical ventilation (LTMV) should take place (^{Phukan & Hardiman, 2009}).

Figure: Philips Cough Assist Mechanical Insufflator-Exsufflator. Image courtesy of Philips Respironics, Murrysville, PA.

LTMV, the most aggressive option for patients with ALS, is not very common in the United States (^{Phukan & Hardiman, 2009}). Some of the reasons for this are patient concerns related to quality of life, financial cost, and disease progression despite the use of mechanical ventilation (^{Elman et al., 2007}). On the other side of the spectrum, there are patients with ALS who may not wish to use any assistive devices or may not be able to tolerate them; these patients should be informed about the terminal phase of ALS and hospice care (^{Miller et al., 2009; Ritsma et al., 2010}).

It is crucial that discussions about treatment options take place before respiratory insufficiency occurs so that patients can take time to think about their options (^{Phukan & Hardiman, 2009}). Clear advance directives are essential to respect patient autonomy and prevent unwanted procedures in the event of a respiratory crisis (^{Elman et al., 2007}). Whatever the circumstance may be, because of the progressive disease process, there comes a time when NIV is no longer effective in controlling symptoms of respiratory insufficiency, or a patient may wish to be taken off of LTMV. A hospice referral to focus on comfort and symptom control is then recommended (^{Miller et al., 2009}). The algorithm for respiratory management recommended by the American Academy of Neurology is provided in Supplemental Digital Content 2, https://links.lww.com/HHN/A8 (^{Miller et al., 2009}).

Patients with ALS are generally best managed in specialized multidisciplinary care centers (^{Wood-Allum & Shaw, 2010}). A team of clinicians which typically includes a neurologist, nurse specialist, pulmonologist, respiratory therapist, occupational therapist, dietician, and a speech pathologist, all working together to support patients' needs (^{Wood-Allum & Shaw, 2010}). As the disease progresses and mobility becomes more difficult, specialty clinics offer an overall advantage of one clinic visit for patient convenience with practitioners who have expertise in caring for patients with ALS (^{Wood-Allum & Shaw, 2010}).

NIV and Its Role in ALS

Noninvasive positive pressure ventilators deliver pressurized gas to the airways through the use of a mask (or “interface”) causing an increase in transpulmonary pressure and inflation of the lungs (^{Mehta & Hill, 2001}). There are a few different types of noninvasive ventilators, which are used, but bilevel noninvasive ventilators are most commonly used on patients with ALS (^{Gregory, 2007}). A bilevel ventilator is a compact computerized device to mechanically assist ventilation, both inspiration and expiration, in patients with respiratory dysfunction. Since 2000, noninvasive positive pressure ventilators have been refined so that patients with neuromuscular diseases such as ALS can use them easily (^{Lechtzin et al., 2004}).

With bilevel NIV, inspiratory positive pressure, expiratory positive pressure, and a backup respiratory rate can be set, and oxygen therapy is rarely needed (^{Gregory, 2007}). It is important for patients with ALS to select a comfortable mask that provides the best seal to prevent air leaks and increase compliance (^{Gregory, 2007}). ALS patients with upper limb weakness or severe bulbar weakness often have difficulties tolerating NIV, but should still be offered treatment (^{Miller et al., 2009}). Aggressive treatment of sialorrhea, excessive salivation, is important for this group of patients using anticholinergics or medications with anticholinergic side effects, such as hyoscyamine, amitriptyline, glycopyrrolate, botulinum toxin injection, and transcutaneous scopolamine (^{Elman et al., 2007; Phukan & Hardiman, 2009}).

NIV is often used solely at nighttime to help with symptoms of sleep-disordered breathing that present with early respiratory insufficiency (^{Elman et al., 2007}). As the disease progresses and an increase in dyspnea occurs, patients may become more dependent on NIV during the daytime (^{Elman et al., 2007}). With increased use of NIV, skin breakdown and nasal stuffiness or dryness can occur (^{Elman et al., 2007}). Alternating masks and providing good skin care with occlusive dressings are then essential nursing interventions (^{Elman et al., 2007}). A humidified air supply may help with nasal dryness or stuffiness (^{Elman et al., 2007}).

^{Heffernan et al. (2006)} reviewed several observational studies regarding the use of NIV in patients with ALS; although they were dated from the 1990s, their results support the use of NIV in patients with ALS. A more recent study by Bourke strongly supports the use of NIV in patients with ALS (^{Miller et al., 2009}). Despite all of the good evidence on the benefits of NIV in patients with ALS, to prolong survival, slow the rate of respiratory insufficiency, and increase quality of life, it remains highly underutilized in the United States and around the world (^{Jackson et al., 2006; Miller et al., 2009}). Females and patients of a low socioeconomic status are less likely to use NIV (^{Lechtzin et al., 2004}). Some of the proposed reasons for this disparity include a lack of access to multidisciplinary care, healthcare provider bias, and patient attitudes regarding health beliefs (^{Lechtzin et al., 2004}). Some factors associated with increased use of NIV in patients with ALS include a higher socioeconomic status, more severe disease, participation in research trials, male gender, and the use of a gastrostomy tube (^{Lechtzin et al., 2004}).

The Benefits of NIV in Patients With ALS

A randomized controlled trial in the United Kingdom explored the effect of NIV on quality of life and survival for patients with ALS (^{Bourke et al., 2006}). All 121 patients with ALS from a single regional center were potentially eligible to be included in the study. Participants were excluded if they had current or past use of NIV, were older than 75 years of age, or were unable to complete assessment scales because of cognitive impairment or inability to communicate with the use of an assistive device.

At enrollment and every 2 months thereafter, both respiratory symptoms and measurements including FVC sitting and supine, maximum inspiratory and expiratory pressures, and sniff nasal inspiratory pressure were recorded. Daytime sleepiness was assessed using the Epworth Sleepiness Scale. ABG sampling was performed in patients who scored greater than 10 points on the Epworth Sleepiness Scale or reported morning headaches. An assessment of the facial muscles commonly used for eating, swallowing, and speaking, known as bulbar function, was categorized using a six-point scale with normal to moderate bulbar impairment rated (4–6), and severe bulbar impairment rated (0–3). Criteria for entrance into the study included orthopnea with a maximum inspiratory pressure less than 60% predicted or symptomatic daytime hypercapnia measured by the Epworth Sleepiness Scale and ABG. The sample consisted of 41 people with ALS who met criteria during the surveillance period from September 2000 to December 2003, and were randomly assigned to receive either NIV or standard care.

After being assigned to either the NIV or the standard care group, an initial assessment of their symptoms, lung function, and quality of life took place, and was subsequently assessed at 1 month, 3 months, and then every 3 months thereafter. All patients were followed up to death, with the exception of one patient who remained alive beyond 45 months. Multiple instruments were used to assess quality of life: the SF36, a generic instrument that includes questions regarding general physical and emotional health perception, pain, and energy vitality; the sleep apnea quality of life index (SAQLI); and the chronic respiratory disease questionnaire (CRQ). Baseline ABG and PSG were completed, which allowed for sleep stage, arousals, apneas, hypopneas, and oxygen saturation levels to be recorded.

Patients in both the NIV and the standard care group were given flu and pneumococcal vaccines and were taught about special cough assist techniques. Education was given to patients in both groups about posture during sleep and adjustable beds were supplied when indicated. All patients had access to palliative care in the terminal phase of their illness.

NIV was initiated in hospital using a bilevel pressure support ventilator. Masks were altered as necessary to increase compliance. A total of 20 patients had normal bulbar function or mild or moderate impairment (12 in the NIV group and 8 in the standard care). There were 21 patients with severe bulbar impairment (11 patients in the NIV group and 10 in the standard care). The ventilator recorded the mean duration of hours used per day, which was 9.3 hours per day in the group with better bulbar function compared with the poor bulbar group at 3.8 hours per day. In the normal and moderate bulbar impairment group who received NIV, the largest benefits were shown in quality of life assessment scales and survival. Median survival in the NIV group with normal and moderate bulbar impairment was 216 days whereas the group of patients who did not receive NIV with normal and moderate bulbar impairment had a median survival of 11 days. Although NIV did not show any benefit in survival in the patients with poor bulbar function, it did show increased quality of life based on the following domains listed in the assessment scales: the CRQ dyspnea, and SAQLI daily functioning, social isolation, and symptoms. The quality of life measures reported in the NIV group maintained above 75% of the baseline for most of the follow-up period not dependent on bulbar function. The greatest improvements in quality of life were reported in problems related to sleep, followed by mental health, energy vitality, and general health perception.

In this investigation, NIV improves survival and increases quality of life for patients with normal to moderately impaired bulbar function. Although NIV did not demonstrate to offer a survival advantage in patients with severe bulbar impairment, these patients should still be offered NIV therapy to improve symptom control and quality of life (^{Bourke et al., 2006}). Although the small sample size is a limitation to the study, the results indicated very positive benefits overall for patients with ALS.

Dyspnea in the Terminal Phase

Patients with ALS are considered to be in the terminal phase of the disease when their life expectancy is less than 6 months (^{McCluskey, 2007}). Dyspnea is one of the most distressing symptoms for patients with ALS (^{Tripodoro & De Vito, 2008}). This troublesome symptom can occur either early or late in the course of the disease and is terrifying for both the patient and their caregivers (^{Currow & Abernathy, 2007; Lo Coco et al., 2006}). A variety of different causes may contribute to dyspnea in patients with ALS some of which include weakness of the respiratory muscles due to the disease process; choking on food, saliva, or liquids; anxiety; exertion; and orthopnea (^{Tripodoro & De Vito, 2008}). Anxiety associated with dyspnea needs to be treated aggressively in patients with ALS (^{Elman et al., 2007}).

As the disease progresses NIV may no longer effectively relieve symptoms of ALS nor provide adequate oxygen exchange to manage symptoms of respiratory insufficiency (^{Elman et al., 2007}). Hospice care is then recommended for patients who are in the terminal stage of the disease (^{Elman et al., 2007; Miller et al., 2009}).

Oxygen Therapy in ALS Patients

In patients with ALS, oxygen therapy alone is not recommended to treat dyspnea because of a potential to increase the arterial pCO₂, which worsens hypoventilation, ultimately contributing to hypoventilatory respiratory failure (^{Elman et al., 2007; Gregory, 2007}). Oxygen is generally provided in the terminal stage of the disease process when symptomatic hypoxia is present (^{Andersen et al., 2007}). Symptoms of hypoxia patients may experience include complaints of air hunger, headache, nausea, fatigue, or dizziness. Cyanosis and rapid breathing are obvious signs of hypoxia in patients with ALS in the terminal stage.

Palliative care research has shown that movement of air across the nasal passages helps to relieve the sensation of dyspnea in patients with refractory dyspnea related to a variety of life-limiting illnesses (^{Abernathy et al., 2010}). Airflow from fans or open windows can stimulate receptors in the face and nasal passages to help decrease the sensation of dyspnea (^{Morrison & Morrison, 2006}).

Pharmacological Management of Dyspnea in ALS Patients

According to ^{Miller et al. (2009)} there is insufficient evidence to support any specific treatment of dyspnea in ALS patients. Treatment of dyspnea is derived from palliative care literature (^{Elman et al., 2007; Morrison & Morrison, 2006; Oxberry & Lawrie, 2009; Tripodoro & De Vito, 2008}). Opioids are the mainstay of treatment for dyspnea in patients who are near and at the end-of-life (^{Elman et al., 2007; Oxberry & Lawrie, 2009}). Opioids relieve dyspnea by decreasing the central perception of air hunger (^{Morrison & Morrison, 2006}). It is well known that dyspnea has psychological and emotional components (^{Morrision & Morrison, 2006}). Benzodiazepines such as lorazepam may be helpful to treat the anxiety associated with not being able to breathe efficiently (^{Elman et al., 2007}).

Nonpharmacological Interventions for Dyspnea in ALS Patients

Nonpharmacological interventions that can be used for the treatment of dyspnea are derived from palliative care and critical care since evidence-based recommendations in ALS literature are not available (^{Bookbinder & McHugh, 2010}). Adjusting patients' position so they are sitting up and leaning forward slightly helps to increase abdominal pressure and improve respiratory muscular function (^{Spector et al., 2007}). Vibration of the patient's chest and electrical stimulation of leg muscles are recommended to help relieve shortness of breath (^{Spector et al., 2007}). A pursed-lip diaphragmatic breathing technique may be helpful to slow down breathing (^{Spector et al., 2007}). Lastly, psychotherapy or relaxation techniques such as massage and music therapy can help relieve the anxiety that often accompanies dyspnea (^{Bookbinder & McHugh, 2010}).

Conclusion

The diagnosis of ALS is devastating for patients and their loved ones. Because there is no known cure, treatment focuses primarily on optimal symptom control. There are many bothersome and distressing symptoms patients with ALS experience, with dyspnea being one of the most feared. It is important that clinicians discuss treatment options to manage respiratory insufficiency early in the course of the disease to assist patients through their disease progression. To respect patient autonomy, early advance directives are essential for patients with ALS before their disease advances into the terminal stage.

Routine assessments of respiratory function should be performed every 3 months for patients with ALS and should include a history, physical exam, and laboratory tests. When signs or symptoms of hypoventilation occur, patients with ALS should be offered NIV as the first line of treatment. NIV can help to improve symptoms of hypoventilation and dyspnea for many patients with ALS who are able to tolerate therapy, and has been shown to prolong survival in patients without severe bulbar weakness. As patients enter into the terminal stage of the ALS disease process, defined by a prognosis of less than 6 months to live, hospice care is recommended to provide additional support for the patient and family through a multidisciplinary team of clinicians.