Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.

Keywords: Amyotrophic lateral sclerosis; airway clearance; respiratory muscles; respiratory therapy; sleep disordered breathing; ventilation.

Figure 1.

Respiratory upper and lower motor neuron degeneration in ALS leads to weakness and atrophy of the inspiratory and expiratory muscles, as well as muscles of the upper airway. Isolated or combined dysfunction of these motor neuron pools leads to hypoventilation, dystussia, and dysphagia in patients.

Figure 2.

Examples of cough spirometry waveforms in an unaffected individual (a) and a person with ALS (b). a) The example from the unaffected individual illustrates clear temporal distinctions between the inspiratory, compression, and expiratory phases of cough. An increased peak inspiratory flow reflects an elevated inspiratory effort to augment the operating volume of the lungs. Peak cough flow (PCF) refers to the peak flow achieved during the expiratory phase of cough and is normal in this example (6.5 L/s). b) The voluntary cough waveform in the ALS subject demonstrates prolonged inspiratory and compression phases, presence of air leaking during compression phase, prolonged time to reach peak cough flow, and a lower absolute expiratory peak flow, which contributed to an ineffective cough (<3 L/s).

Figure 3.

Schematic illustrates MI-E pressure and timing, as compared to bilevel, positive pressure ventilation. A single MI-E set alternates positive insufflation pressure and brief inspiratory hold, with rapid application of negative exsufflation pressure. The inspiratory and expiratory holds, along with pauses between I-E cycles, can be customized to correspond to the patient’s spontaneous breath timing. I-E cycles are frequently repeated a few times in a single I-E set, and multiple I-E sets are typically performed in a single assisted airway clearance session.

Figure 4.

Respiratory strength training is typically accomplished using portable devices that impose an external load to the muscles of inspiration or expiration. Right image: pressure-threshold devices typically use a calibrated spring and valve that blocks either inspiration or expiration. To open the valve, the patient must exert an increased effort to generate enough pressure to overcome the tension exerted by the spring. Left image: respiratory loads can also be delivered via flow resistance. Uncontrolled resistive loads, such as straw or impeded snorkel-breathing, can be minimized with a slow breath pattern with low airflows. To overcome this issue, some devices incorporate electronic braking algorithms capable of delivering a consistent, proportional load throughout the breath volume.

Figure 5.

AIH protocols consist of several (typically 5–15) short intervals of breathing mildly lowered oxygen, interspersed with breathing normal air. Hypoxia durations used in patient populations vary from 1–4 min in duration and are typically between 9–12% oxygen, which is equivalent to altitudes found at Pike’s Peak (∼12.3% O₂) to Mount Denali (∼9.7% O₂). Periods of normoxia (21% O₂) may differ between patient populations, but typically last between 1-4 min. Researchers have used custom-mixed gas bags or commercially-available altitude simulators to deliver lowered oxygen air at the desired concentration. The effects of single AIH sessions may emerge 30–60 min after the last hypoxic interval and may last for several hours.