Alveolar Ventilation-Targeted Versus Spontaneous/Timed Mode for Home Noninvasive Ventilation in Amyotrophic Lateral Sclerosis
=============================================================================================================================

* Pattaraporn Panyarath
* Veronique Adam
* R John Kimoff
* Marta Kaminska

## Abstract

**BACKGROUND:** Home noninvasive ventilation (NIV) is increasingly used in amyotrophic lateral sclerosis (ALS) to improve symptoms and survival. Our primary objective was to compare intelligent volume-assured pressure support (iVAPS) versus spontaneous/timed (S/T) modes regarding time to first change in ventilator parameters and the number of interventions over 6 months in subjects with ALS in a respiratory therapist (RT)-led program.

**METHODS:** In this study, 30 subjects with ALS meeting criteria for NIV initiation were randomized to iVAPS or S/T. NIV was initiated using standardized protocols targeting optimal tidal volume and comfort in a daytime session. Download data were recorded at 1 week and 1 and 6 months. Any changes in ventilator parameters were recorded.

**RESULTS:** Of the 30 subjects, 56.7% had bulbar onset ALS, 8 died, and 11 in each group completed the study. Median time to first parameter change was 33.5 (interquartile range [IQR] 7.7–96.0) d versus 41.0 (IQR 12.5–216.5) d for iVAPS versus S/T groups, respectively, *(P* = .48). The average number of RT interventions was similar between groups (1.1 ± 1.1 vs 0.9 ± 0.9 at 1 month, *P* = .72; 2.4 ± 2.1 vs 2.4 ± 2.3 at 6 months, *P* = .95, for iVAPS vs S/T, respectively). Adherence was significantly lower with iVAPS than S/T at 1 week but not at 1 or 6 months. Download parameters were similar between groups at 1 week and 6 months except for higher residual apnea-hypopnea index (AHI) and less spontaneously triggered breaths with iVAPS at 6 months.

**CONCLUSIONS:** The time to first change of parameters and the number of interventions at 6 months from NIV initiation were similar for the iVAPS and S/T modes in subjects with ALS. With iVAPS, adherence was lower transiently at NIV initiation, and the residual AHI was higher at 6 months. Alveolar ventilation-targeted NIV may require a longer adaptation period and result in greater upper-airway instability predominantly in patients with bulbar ALS.

*   noninvasive ventilation (NIV)
*   intelligent volume-assured pressure support (iVAPS)
*   bi-level spontaneous timed ventilation
*   amyotrophic lateral sclerosis (ALS)
*   respiratory therapist interventions
*   apnea-hypopnea index

## Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is incurable and leads to progressive respiratory muscle weakness.1 A recent systematic review and meta-analysis demonstrated that the overall worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92–4.96) per 100,000 population and 1.59 (95% CI 1.39–1.81) per 100,000 person-y, respectively.2 The most common causes of death in patients with ALS are chronic hypercapnic respiratory failure, airway obstruction by secretions due to ineffective cough, and aspiration pneumonia.3,4 Home noninvasive ventilation (NIV) is increasingly used in patients with ALS for improving respiratory function, health-related quality of life, and survival.5-18 The randomized controlled trial (RCT) by Bourke and colleagues showed that NIV improves survival and quality of life in subjects with ALS with orthopnea, maximum inspiratory pressure < 60% of predicted or symptomatic hypercapnia, but without severe bulbar dysfunction.10 No new RCT has been published in subjects with ALS addressing survival and quality of life with NIV.19 However, the recent well-designed retrospective study by Ackrivo and colleagues demonstrated that NIV was associated with a 26% reduction in mortality, particularly in the limb-onset ALS subtype and with NIV use ≥ 4 h/d.18 Subjects with limb-onset ALS were more likely to tolerate NIV compared to subjects with bulbar-onset ALS (odds ratio 6.25 [95% CI 1.09–33.33]).6,20 Recently, a prospective study reported that NIV conferred a significant survival advantage even in those with severe bulbar impairment with median survival of 13 months compared with 3 months in those not using NIV (*P* < .001). However, bulbar impairment was a cause of NIV failure in 49% of cases and a major prognostic factor.21

Recently, the Canadian Thoracic Society published guidelines for long-term NIV in patients with ALS.22 They suggested earlier initiation of NIV in ALS compared with previous guidelines based on studies suggesting that earlier initiation of NIV in patients with ALS results in improved rate of decline in respiratory function, survival, and quality of life.10,23,24 Data remain limited regarding optimal ventilation modes and parameters, and no recommendation could be made regarding volume-assured pressure support (VAPS) modes of NIV. The intelligent VAPS (iVAPS) is an adaptive ventilation mode that uses an algorithm to adjust pressure support to target a specified alveolar ventilation.25 It has a learning mode that uses the baseline awake ventilation to determine the settings for ventilation.

Several RCTs showed similar efficacy of iVAPS compared to standard pressure support ventilation (PSV) on improving gas exchange, pulmonary function, sleep disturbances, and adherence in individuals with obstructive or restrictive lung disease with chronic hypoventilation.26-32 Interestingly, one RCT showed that the adherence to iVAPS over 1 month was better than standard PSV in a mixed population (5.4 vs 4.2 h/night for iVAPS vs PSV; *P* < .01). iVAPS delivered a lower median pressure support compared with standard PSV.32 The principle of iVAPS is theoretically well suited for ALS due to its adaptive response that obviates the need for overnight NIV titration and its ability to react to progressively deteriorating spontaneous respiratory function over time. Progression of ventilatory failure may result in recurrent periods of inadequate ventilation if parameter adjustments cannot be made, with reduced quality of life and more stress related to respiratory or sleep-related symptoms.33-35 Hence, a device that can be titrated in a daytime trial and would self-adjust automatically over time as respiratory muscle weakness progresses could be beneficial for patient-related outcomes and could be more cost effective. On the other hand, patients with ALS may have difficulty tolerating NIV and may require an adaptation period with progressive increase in NIV support.32 A recent retrospective study comparing iVAPS to standard PSV in subjects with ALS showed that iVAPS provided more reliable target tidal volume (VT) than PSV and was associated with decreased rapid shallow breathing index (f/VT) as an indicator of work of breathing.36 However, whether iVAPS results in fewer respiratory therapist interventions related to NIV than standard pressure modes has not been studied. Therefore, the primary aim of this study was to compare iVAPS and spontaneous/timed (S/T) modes in subjects with ALS with respect to time to first change in ventilator parameters and the number of interventions over 6 months, following daytime NIV initiation in the context of a respiratory therapist (RT)–led home ventilation program.

### QUICK LOOK

#### Current Knowledge

Home noninvasive ventilation (NIV) is increasingly used in amyotrophic lateral sclerosis (ALS) and improves symptoms and survival. The intelligent volume-assured pressure support (iVAPS) is an adaptive NIV mode that targets alveolar ventilation and might be helpful for ALS in the context of progressively deteriorating respiratory function over time. Previous studies demonstrated that the iVAPS might impact comfort and adherence to treatment in patients with neuromuscular disease with hypoventilation.

#### Contributes to our knowledge

In this pilot trial, iVAPS did not require fewer interventions or parameter adjustments than the spontaneous/timed mode over 6 months from NIV initiation in a group of subjects with ALS, including a large proportion of individuals with bulbar-onset ALS. Adherence to iVAPS was transiently lower, suggesting that this mode may require a longer adaptation period in patients with ALS. Adherence and subject symptoms were similar with both NIV modes.

## Methods

We performed a pilot RCT with recruitment from February 2014–September 2018 of patients referred for home NIV to the National Program for Home Ventilatory Assistance (NPHVA or Program National d’Assistance Ventilatoire á Domicile, PNAVD) of the McGill University Health Centre (MUHC). Consecutive patients with ALS meeting criteria for NIV initiation were approached. Criteria for NIV were the presence of hypoventilation symptoms and at least one criterion such as daytime hypercapnia (PaCO2 > 45 mm Hg), orthopnea, nocturnal hypoventilation (PCO2 during sleep increase > 10 mm Hg compared with awake PCO2 or nocturnal oxygen desaturation < 88% for a period of at least 5 consecutive min), FVC < 50% of predicted, sniff nasal inspiratory pressure (SNIP) < −40 cm H2O, or PImax < −40 cm H2O. Patients were excluded if they had other major neurological disorders or active cancer, were referred from hospital and were already on a mechanical ventilator, or could not provide informed consent. This study has been registered on ClinicalTrials.gov ([NCT01746381](http://rc.rcjournal.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01746381&atom=%2Frespcare%2F67%2F9%2F1109.atom)). The MUHC Research Ethics Board approved the study protocol. All subjects gave written informed consent.

Subjects with ALS were randomized 1:1 to iVAPS or S/T mode, both with a ResMed Stellar 150 ventilator (ResMed, San Diego, California). Randomization was performed using numbered sealed opaque envelopes based on a random sequence generator. NIV was initiated by an experienced RT using standardized protocols targeting optimal VT and comfort in a daytime session in an out-patient day hospital setting lasting approximately 3 h. Subjects were encouraged to sleep while titration was ongoing if possible. For subjects randomized to S/T mode, expiratory positive airway pressure (EPAP) was set at 5 cm H2O, pressure support was adjusted to achieve optimal VT (8 mL/ideal body weight) if tolerated, and the backup frequency was set just below the subject’s spontaneous breathing frequency, aiming to maximize the subject’s comfort. For those randomized to iVAPS, the learning mode was used to determine the target alveolar ventilation as per the manufacturers protocol.25 The RT selected the 5-min window where the subject’s ventilation and breathing frequency looked stable to set up target alveolar ventilation and backup frequency (as per the “intelligent backup rate” algorithm). Parameters were then tested and adjusted if needed by increasing the minimum level of pressure support to target VT of 8 mL/ideal body weight and for the subject’s comfort. The RT also adjusted inspiratory time, rise time, fall time, trigger sensitivity, and cycle sensitivity for each subject’s comfort in both iVAPS and S/T groups. If a subject fell asleep during the trial and obstructive events were noted, EPAP was raised manually for both S/T and iVAPS modes. For all subjects, the RT recorded vital signs, oxygen saturation (SpO2), and capillary blood gases before the trial of ventilation. All subjects underwent spirometry37 and a SNIP test,38-39 including SNIPopen and SNIPclosed40 at baseline.

The RT visited all subjects at home at 1 week and at 1 and 6 months after NIV initiation. Download parameters such as adherance data (hours of daily usage), air leak, ventilator pressures used, minute ventilation, and respiratory events were recorded. Adjustments to ventilator settings were made if deemed necessary to optimize ventilation, minimize the apnea-hypopnea index (AHI), and maximize comfort and subject symptoms for both iVAPS and S/T groups. Adjustments could be initiated by the RT with pulmonologist approval or by the supervising pulmonologist based on downloaded data. Any changes were recorded. In addition, daytime SpO2 and end-tidal CO2 (EtCO2) were measured at baseline, 1 month, and 6 months. Overnight oximetry also was assessed at 1 month and 6 months using the Rad-8, Masimo SET (Masimo, Irvine, California). Health-related quality of life was assessed at baseline and 3 months using the Severe Respiratory Insufficiency (SRI) questionnaires (scores range from 0–100, with higher scores indicating a better quality of life).41 Participants’ sleep-related symptoms and ventilator satisfaction were assessed at baseline and 6 months using our own questionnaire (see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)).

## Statistical Analysis

The sample size for this pilot study was calculated based on the expected number of ventilator changes over 6 months. We assumed a difference of 2 interventions between the study arms and an SD of 1.5. We would then need 10 subjects per group to detect this difference with alpha 0.05 and power 80%. To account for withdrawal from the study or premature death, the total planned sample size was 30 subjects. Descriptive statistics were provided for each group. Continuous variables were reported as mean and SD. Binary and categorical variables were summarized using frequency counts and percentages. Comparisons of continuous variables were performed using the *t* test and of categorical variables with the chi square test. Pearson correlation was used to determine variables associated with adherence to NIV. Time to first ventilator change was analyzed using survival analysis and Kaplan-Meyer plots with a log-rank test. A *P* value of < .05 was considered statistically significant. All analyses were carried out using SPSS software, version 27 (IBM, Armonk, NY).42

## Results

Five hundred fifty-five patients with ALS were referred to the NPHVA between February 2014–September 2018. Of these, 289 patients were ineligible on the basis of not meeting criteria for NIV initiation, and 236 patients declined to participate in the study. Thirty subjects were randomized to iVAPS or S/T mode. One subject crossed over from iVAPS to S/T due to intolerance at NIV initiation. At 6 months, a total of 3 and 5 subjects died in the iVAPS and S/T groups, respectively. There remained 11 subjects in each group who completed follow-up at 6 months (Fig. 1). Participants’ mean age was 62.8 ± 9.5 y, and 53.3% were male (Table 1). Most subjects were non-obese. Over half (56.7%) of the subjects had bulbar onset ALS. A minority (13.3%) of subjects had feeding tubes. Most subjects had daytime normocapnia (PaCO2 = 42.5 ± 3.8 mm Hg) and normal oxygen saturation (SpO2 = 95.9 ± 2.4%) at NIV initiation. On average, the subjects had moderately severe restrictive lung disease based on FVC (55.4 ± 17.8% of predicted at enrollment). At baseline, no significant differences in demographics, health-related quality of life (SRI), gas exchange, and pulmonary function were observed between iVAPS and S/T groups except for higher proportions of wheelchair users and pregabalin users in the S/T group and higher daytime PaCO2 in the iVAPS group (Table 1).

![Fig. 1.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/67/9/1109/F1.medium.gif)

[Fig. 1.](http://rc.rcjournal.com/content/67/9/1109/F1)

Fig. 1. 
Flow chart. iVAPS = intelligent volume-assured pressure support; S/T = spontaneous/timed.

View this table:
[Table 1.](http://rc.rcjournal.com/content/67/9/1109/T1)

Table 1. 
Baseline Demographics, Blood Gas, and Pulmonary Function Parameters for Subjects With Amyotrophic Lateral Sclerosis Using Intelligent Volume-Assured Pressure Support Versus Spontaneous/Timed Modes

Table 2 shows the ventilator settings in iVAPS and S/T groups at 1 week, 1 month, and 6 months. At 1 week, the backup frequency was significantly higher in the iVAPS group at 15.4 versus 11.4 breaths/min for iVAPS versus S/T groups, respectively, (*P* = .004). Adherence to NIV was significantly lower with iVAPS than S/T at 1 week (Table 3). At 1 week, 13.2% of participants in the iVAPS group was using NIV ≥ 4 h/night compared with 45.4% using S/T (*P* = .033). The average duration of NIV use at 1 week was 2.2 and 4.6 h/night for iVAPS versus S/T groups, respectively, (*P* = .034). However, there were no significant differences in NIV adherence between groups at 1 and 6 months. (Table 3). Download parameters were similar between groups at 1 week, 1 month, and 6 months (Table 3) except for significantly higher residual AHI and hypopnea index with iVAPS at all time points and less spontaneously triggered breaths with iVAPS at 6 months, possibly related to differences in trigger sensitivity. To assess if the AHI is related to variability in ventilation, we calculated Pearson correlation coefficients between the residual AHI and the difference between 95th percentile and median inspiratory positive airway pressure (Δ IPAP) for the iVAPS group. Then we found no significant relationship between the residual AHI and the Δ IPAP for the iVAPS group at any time point: r = 0.494, *P* = .09 at 1 week; r = 0.176, *P* = .57 at 1 month; and r = 0.089, *P* = .81 at 6 months (Figure S1, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)). However, we found significant correlations between the residual AHI and the difference between 95th percentile and median VT (Δ VT) for the iVAPS group at 1 and 6 months (r = 0.480, *P* = .08 at 1 week; r = 0.683, *P* = .007 at 1 month; and r = 0.706, *P* = .01 at 6 months) (Figure S1). In exploratory analyses, we divided subjects into bulbar and non–bulbar onset ALS. We observed a significantly higher residual AHI with iVAPS only at 1 month in subjects with bulbar-onset ALS (Tables S1 and S2, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)), though nonsignificant differences occurred in both groups at other time points. We used the rapid shallow breathing index (f/VT) to evaluate the work of breathing in subjects on NIV. We found no significant difference in f/VT during NIV use between groups over 6 months (Table 3). In this cohort, mask leak did not differ significantly between iVAPS and S/T (Table 3). We also found no significant relationships between average hours of NIV use and demographics, gas exchange parameters, download parameters, mask changes, or lung function parameters except for an inverse relationship with SNIPopen (r = −0.55, *P* = .02) (Table 4).

View this table:
[Table 2.](http://rc.rcjournal.com/content/67/9/1109/T2)

Table 2. 
Noninvasive Ventilation Settings and Type of Mask at 1 Week, 1 Month, and 6 Months

View this table:
[Table 3.](http://rc.rcjournal.com/content/67/9/1109/T3)

Table 3. 
Download Parameters of Noninvasive Ventilation at 1 Week, 1 Month, and 6 Months

View this table:
[Table 4.](http://rc.rcjournal.com/content/67/9/1109/T4)

Table 4. 
Association Between Noninvasive Ventilation Adherence (Daily Use, All Days) and Other Variables at 6 Months

As shown in Figure 2, the median time to first ventilator parameters change was 33.5 (IQR 7.7–96.0) d versus 41.0 (IQR 12.5–216.5) d for iVAPS versus S/T groups, respectively, *(P* = .48 by log-rank test). The average number of RT interventions was similar between iVAPS and S/T groups at 1 month and 6 months (1.1 ± 1.1 vs 0.9 ± 0.9 at 1 month, *P* = .72; 2.4 ± 2.1 vs 2.4 ± 2.3 at 6 months, *P* = .95, for iVAPS vs S/T, respectively). The characteristics of interventions were similar in both groups except for more increases in trigger sensitivity with S/T (Table 5). No significant difference in interventions to optimize mask fit between iVAPS and S/T groups was observed. At 6 months, 3 and 5 subjects died in the iVAPS and S/T groups, respectively, (Chi square, *P* = .54), all from respiratory failure.

![Fig. 2.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/67/9/1109/F2.medium.gif)

[Fig. 2.](http://rc.rcjournal.com/content/67/9/1109/F2)

Fig. 2. 
Kaplan-Meier curves for time to first change in ventilator settings according to ventilator mode. S/T = spontaneous/timed; iVAPS = intelligent volume-assured pressure support.

View this table:
[Table 5.](http://rc.rcjournal.com/content/67/9/1109/T5)

Table 5. 
Characteristics of Respiratory Interventions Over 6-Month Follow-Up

Most subjects had normal daytime oxygen saturation and EtCO2 at baseline, 1 month, and 6 months. We found that daytime oxygen saturation and EtCO2 in iVAPS were similar to the S/T group from NIV initiation to 1 month and 6 months follow-up (Table S3, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)). Six participants underwent overnight oximetry at 1 month and 6 months in iVAPS and S/T groups. We found no difference in the mean or nadir SpO2 during sleep, 4% oxygen desaturation index, and percentage time with oxygen saturation < 90% from 1 month to 6 months between iVAPS and S/T groups (Table S3). We also observed no significant difference in participant’s sleep-related symptoms between iVAPS and S/T groups from NIV initiation to 6 months follow-up (Table S4, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)). According to the SRI questionnaires, there was no significant difference in health-related quality of life between iVAPS and S/T group in change from baseline to 3 months except that the respiratory-complaint component deteriorated significantly in the S/T group but not in the iVAPS group (Table S5, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)). In addition, no significant difference in participant-reported ventilator comfort and satisfaction was observed between iVAPS and S/T groups at 1 and 6 months (Table S6, see related supplementary materials at [http://www.rcjournal.com](http://www.rcjournal.com)).

## Discussion

In this study, we found that time to first ventilator parameter change and number and type of RT interventions over 6 months were similar in subjects with ALS using iVAPS and S/T modes of NIV. This study demonstrated that the iVAPS mode did not require fewer interventions than the S/T mode over 6 months from NIV initiation. The iVAPS mode was as effective as standard S/T pressure ventilation when initiated by a highly skilled RT in a home ventilation program with respect to physiologic and patient-related outcomes. We also found ventilator download parameters, daytime gas exchange, ventilator comfort, and respiratory symptoms to be similar between groups except for higher residual AHI on iVAPS. These findings support the previous studies comparing VAPS with standard PSV in subjects with neuromuscular disease.28,43

Interestingly, we found that adherence was significantly lower with iVAPS than S/T at 1 week but not at 1 or 6 months. Jaye and colleagues had found no significant difference in adherence between auto-titrating and standard PSV in neuromuscular disease.28 On the other hand, this finding is contrary to the previous RCT by Kelly and colleagues, which suggested that the adherence to iVAPS over 1 month was better than standard PSV and lower median pressure support with iVAPS in a mixed population.32 Although we demonstrated that alveolar ventilation-targeted NIV may require a longer adaptation period, there was no significant difference in adherence or survival between iVAPS and S/T at 6 months among our subjects with ALS. We hypothesize that a longer adaptation period may be needed in subjects with ALS with bulbar impairment to the iVAPS mode that is inherently less stable than the S/T mode. Patients with bulbar symptoms may be more prone to reflex laryngospasm,44-46 glottic closure, or discoordination with more variable pressure, but we have not assessed this systematically. An important element associated with adherence to NIV is adequate mask fit. Whereas there were more mask changes in the S/T group in our study, the difference was not statistically significant, and similar proportions of subjects used facial versus nasal masks in each group. We found no significant relationship between NIV adherence and mask changes (Table 4). Irrespective of NIV mode, adherence was related to lower SNIP (Table 4), which suggests that greater diaphragm weakness is the main factor driving patients with ALS to use NIV.

Nicholson and colleagues36 found that adequate VT were more reliably attained for iVAPS compared with PSV in subjects with ALS. However, we found no significant difference in median VT between iVAPS and S/T modes over 6 months. They also reported a significantly lower rapid shallow breathing index with iVAPS compared to PSV, whereas we found no difference. This may be due to differences in the study populations (more bulbar symptoms and higher FVC in our study population) and in the effectiveness of the parameters set for the S/T mode. In our study, participants in the S/T group achieved higher VT and a lower rapid shallow breathing index than the S/T group in the Nicholson study.

The learning mode in iVAPS uses the patient’s respiratory pattern to set the ventilation parameters. In patients with ALS, it is prone to “learning” the patient’s dysfunctional rapid shallow breathing pattern that results from respiratory muscle weakness. It would then apply inadequate NIV settings with underestimated pressure support. Both the Nicholson and our study protocols have ensured the minimum pressure support setting is manually corrected if needed to provide sufficient VT.

Previous studies reported that subjects with limb-onset ALS were more likely to tolerate NIV compared with subjects with bulbar-onset ALS.10,11,20 We found no significant relationships between average hours of NIV use and type of onset of ALS. That is, adherence was no different for bulbar versus non–bulbar subjects. Several studies showed bulbar-onset ALS had a greater risk for upper-airway obstruction during sleep.34,47,48 We found significantly higher residual AHI in subjects using iVAPS, primarily but not exclusively in subjects with bulbar-onset ALS. We hypothesize that the iVAPS mode, with fluctuating levels of pressure support, might result in greater upper-airway instability predominantly in individuals with bulbar ALS. Moreover, the iVAPS mode may have resulted in transient intermittent overventilation and hypocapnia that resulted in central or obstructive hypopneas, despite relatively low levels of pressure support. This hypothesis is supported by our finding of significant correlations between the residual AHI and Δ VT for the iVAPS group. Larger studies, ideally with polysomnographic confirmation, will be needed to confirm this hypothesis.

The strength of our study is that we studied subjects with ALS for a period of 6 months, though with several deaths during the study period. We assessed a wide range of outcomes, and although this has led to multiple comparisons, results should be seen as exploratory for this pilot study. There were some limitations to our study. First, participants and RTs were not blinded to the intervention, which may have introduced bias. However, this would have been expected to result in fewer interventions or longer time to interventions in the iVAPS mode, which was not the case. Second, our findings were based on a small sample of subjects because of its pilot nature. Third, we did not evaluate quality of life in our subjects at 6 months because most subjects refused to do the SRI questionnaires at 6 months and some subjects died before 6 months of follow-up. Furthermore, unexpectedly, over half of the subjects had bulbar-onset ALS. These results might, therefore, not be representative of a more typical group of patients with ALS with a larger proportion of non–bulbar-onset initiating NIV. There were other unbalanced baseline characteristics between groups that may have impacted results such as medication differences and statistically but not clinically important PaCO2 differences. Additionally, we did not evaluate baseline polysomnography to evaluate the prevalence of sleep-disordered breathing before NIV initiation, nor were sleep-disordered breathing and gas exchange assessed in all patients on NIV at follow-up. A future larger randomized control study comparing iVAPS with standard S/T mode with overnight gas exchange monitoring at baseline and follow-up would be useful to better understand differences between the 2 modes in both subjects with bulbar and non–bulbar-onset ALS. Finally, this study was conducted in the context of a large, well-established home ventilation program staffed by highly trained and experienced RTs accustomed to working with the ALS population. Conceivably, the iVAPS mode could provide advantages for adaptation to therapy over S/T in other clinical contexts, although further research would be required to specifically address this question.

## Conclusions

The iVAPS mode did not require fewer interventions than the S/T mode over 6 months from NIV initiation in subjects with ALS. With iVAPS, adherence was transiently lower at NIV initiation, and the residual AHI was higher at 6 months. Alveolar ventilation-targeted NIV may require a longer adaptation period and result in greater upper-airway instability in patients with ALS.

## ACKNOWLEDGMENTS

We would like to thank the whole team of the Quebec NPHVA, MUHC, Montreal, Quebec, Canada. We would like to acknowledge Dr Lancelot Pinto for his work on developing the questionnaires for the study.

## Footnotes

*   Correspondence: Pattaraporn Panyarath MD, McGill University Health Centre, Respiratory Division/Sleep laboratory, 1001 Decarie Boulevard, Montreal, Quebec, Canada, H4A 3J1. E-mail: pattaraporn.panyarath{at}mail.mcgill.ca
*   The authors have disclosed a relationship with ResMed.

*   This study was funded by an unrestricted grant and in-kind (ventilator device) support from ResMed. ResMed had no input in the design, conduct, analysis, or publication of this study.

*   This study was performed at McGill University Health Centre and Quebec National Program for Home Ventilatory Assistance, Montreal, Quebec, Canada.

*   Supplementary material related to this paper is available at [http://www.rcjournal.com](http://www.rcjournal.com).

*   Copyright © 2022 by Daedalus Enterprises

## References

1.  1.Munsat TL, Andres PL, Finison L, Conlon T, Thibodeau L. The natural history of motoneuron loss in amyotrophic lateral sclerosis. Neurology 1988;38(3):409-413.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1212/WNL.38.3.409&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=3347345&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

2.  2.Xu L, Liu T, Liu L, Yao X, Chen L, Fan D, et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol 2020;267(4):944-953.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1007/s00415-019-09652-y&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

3.  3.Radunović A, Mitsumoto H, Leigh PN. Clinical care of patients with amyotrophic lateral sclerosis. Lancet Neurol 2007;6(10):913-925.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1016/S1474-4422(07)70244-2&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=17884681&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000250035600021&link_type=ISI) 

4.  4.Howard RS, Wiles CM, Loh L. Respiratory complications and their management in motor neuron disease. Brain 1989;112 Pt(5):1155-1170.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1093/brain/112.5.1155&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=2804610&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=A1989AY17400003&link_type=ISI) 

5.  5.Piper AJ, Sullivan CE. Effects of long-term nocturnal nasal ventilation on spontaneous breathing during sleep in neuromuscular and chest wall disorders. Eur Respir J 1996;9(7):1515-1522.
    
    [Abstract/FREE Full Text](http://rc.rcjournal.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiZXJqIjtzOjU6InJlc2lkIjtzOjg6IjkvNy8xNTE1IjtzOjQ6ImF0b20iO3M6MjQ6Ii9yZXNwY2FyZS82Ny85LzExMDkuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

6.  6.Aboussouan LS, Khan SU, Meeker DP, Stelmach K, Mitsumoto H. Effect of noninvasive positive-pressure ventilation on survival in amyotrophic lateral sclerosis. Ann Intern Med 1997;127(6):450-453.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.7326/0003-4819-127-6-199709150-00006&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=9313002&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=A1997XV77900006&link_type=ISI) 

7.  7.Pinto AC, Evangelista T, Carvalho M, Alves MA, Sales Luís ML. Respiratory assistance with a noninvasive ventilator (BiPAP) in MND/ALS patients: survival rates in a controlled trial. J Neurol Sci 1995;129 Suppl:19-26.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1016/0022-510X(95)00052-4&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=7595610&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=A1995RK08500005&link_type=ISI) 

8.  8.Sancho J, Servera E, Morelot-Panzini C, Salachas F, Similowski T, Gonzalez-Bermejo J. Noninvasive ventilation effectiveness and the effect of ventilatory mode on survival in ALS patients. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(1-2):55-61.
    
    

9.  9.Khamankar N, Coan G, Weaver B, Mitchell CS. Associative increases in amyotrophic lateral sclerosis survival duration with noninvasive ventilation initiation and usage protocols. Front Neurol 2018;9:578.
    
    

10. 10.Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of noninvasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomized controlled trial. Lancet Neurol 2006;5(2):140-147.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1016/S1474-4422(05)70326-4&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=16426990&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000234914800018&link_type=ISI) 

11. 11.Bourke SC, Bullock RE, Williams TL, Shaw PJ, Gibson GJ. Noninvasive ventilation in ALS: indications and effect on quality of life. Neurology 2003;61(2):171-177.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1212/01.WNL.0000076182.13137.38&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=12874394&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

12. 12.Lyall RA, Donaldson N, Fleming T, Wood C, Newsom-Davis I, Polkey MI, et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 2001;57(1):153-156.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=11445650&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

13. 13.Jackson CE, Rosenfeld J, Moore DH, Bryan WW, Barohn RJ, Wrench M, et al. A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients. J Neurol Sci 2001;191(1-2):75-78.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1016/S0022-510X(01)00617-7&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=11676995&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000172104500011&link_type=ISI) 

14. 14.Lo Coco D, Marchese S, Pesco MC, La Bella V, Piccoli F, Lo Coco A. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival. Neurology 2006;67(5):761-765.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1212/01.wnl.0000227785.73714.64&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=16899545&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

15. 15.Sheers N, Berlowitz DJ, Rautela L, Batchelder I, Hopkinson K, Howard ME. Improved survival with an ambulatory model of noninvasive ventilation implementation in motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(3-4):180-184.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

16. 16.Gonzalez Calzada N, Prats Soro E, Mateu Gomez L, Giro Bulta E, Cordoba Izquierdo A, Povedano Panades M, et al. Factors predicting survival in amyotrophic lateral sclerosis patients on noninvasive ventilation. Amyotroph Lateral Scler Frontotemporal Degener 2016;17(5-6):337-342.
    
    

17. 17.Berlowitz DJ, Howard ME, Fiore JF Jr., Vander Hoorn S, O'Donoghue FJ, Westlake J, et al. Identifying who will benefit from noninvasive ventilation in amyotrophic lateral sclerosis/motor neuron disease in a clinical cohort. J Neurol Neurosurg Psychiatry 2016;87(3):280-286.
    
    [Abstract/FREE Full Text](http://rc.rcjournal.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI4Ny8zLzI4MCI7czo0OiJhdG9tIjtzOjI0OiIvcmVzcGNhcmUvNjcvOS8xMTA5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

18. 18.Ackrivo J, Hsu JY, Hansen-Flaschen J, Elman L, Kawut SM. Noninvasive ventilation use is associated with better survival in amyotrophic lateral sclerosis. Ann Am Thorac Soc 2021;18(3):486-494.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

19. 19.Radunovic A, Annane D, Rafiq MK, Brassington R, Mustfa N. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2017;10(10):CD004427.
    
    

20. 20.Gruis KL, Brown DL, Schoennemann A, Zebarah VA, Feldman EL. Predictors of noninvasive ventilation tolerance in patients with amyotrophic lateral sclerosis. Muscle Nerve 2005;32(6):808-811.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1002/mus.20415&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=16094653&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

21. 21.Sancho J, Martínez D, Bures E, Díaz JL, Ponz A, Servera E. Bulbar impairment score and survival of stable amyotrophic lateral sclerosis patients after noninvasive ventilation initiation. ERJ Open Res 2018;4(2):00159-2017.
    
    

22. 22.Rimmer KP, Kaminska M, Nonoyama M, Giannouli E, Maltais F, Morrison DL, et al. Home mechanical ventilation for patients with amyotrophic lateral sclerosis: a Canadian Thoracic Society clinical practice guideline. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine 2019;3(1):9-27.
    
    

23. 23.Pinto A, de Carvalho M, Evangelista T, Lopes A, Sales-Luís L. Nocturnal pulse oximetry: a new approach to establish the appropriate time for noninvasive ventilation in ALS patients. Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4(1):31-35.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1080/14660820310006706&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=12745616&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000182593500008&link_type=ISI) 

24. 24.Lechtzin N, Scott Y, Busse AM, Clawson LL, Kimball R, Wiener CM. Early use of noninvasive ventilation prolongs survival in subjects with ALS. Amyotroph Lateral Scler 2007;8(3):185-188.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1080/17482960701262392&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=17538782&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000246949600009&link_type=ISI) 

25. 25.ResMed. Getting started on iVAPS. August 2011. Available at: [https://document.resmed.com/documents/products/machine/stellar-series/fact-sheet/1014300\_getting-started-on-ivaps\_fact-sheet\_anz\_eng.pdf](https://document.resmed.com/documents/products/machine/stellar-series/fact-sheet/1014300\_getting-started-on-ivaps_fact-sheet_anz_eng.pdf). Accessed November 1, 2013.
    
    

26. 26.Ekkernkamp E, Storre JH, Windisch W, Dreher M. Impact of intelligent volume-assured pressure support on sleep quality in stable hypercapnic chronic obstructive pulmonary disease patients: a randomized crossover study. Respiration 2014;88(4):270-276.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

27. 27.Oscroft NS, Ali M, Gulati A, Davies MG, Quinnell TG, Shneerson JM, et al. A randomized crossover trial comparing volume-assured and pressure-preset noninvasive ventilation in stable hypercapnic COPD. COPD 2010;7(6):398-403.
    
    

28. 28.Jaye J, Chatwin M, Dayer M, Morrell MJ, Simonds AK. Auto-titrating versus standard noninvasive ventilation: a randomized crossover trial. Eur Respir J 2009;33(3):566-571.
    
    [Abstract/FREE Full Text](http://rc.rcjournal.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiZXJqIjtzOjU6InJlc2lkIjtzOjg6IjMzLzMvNTY2IjtzOjQ6ImF0b20iO3M6MjQ6Ii9yZXNwY2FyZS82Ny85LzExMDkuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

29. 29.Nilius G, Katamadze N, Domanski U, Schroeder M, Franke KJ. Noninvasive ventilation with intelligent volume-assured pressure support versus pressure-controlled ventilation: effects on the respiratory event rate and sleep quality in COPD with chronic hypercapnia. Int J Chron Obstruct Pulmon Dis 2017;12:1039-1045.
    
    

30. 30.McArdle N, Rea C, King S, Maddison K, Ramanan D, Ketheeswaran S, et al. Treating chronic hypoventilation with automatic adjustable versus fixed EPAP intelligent volume-assured positive airway pressure support (iVAPS): a randomized controlled trial. Sleep 2017:40(10).
    
    

31. 31.Orr JE, Coleman J, Criner GJ, Sundar KM, Tsai SC, Benjafield AV, et al. Automatic EPAP intelligent volume-assured pressure support is effective in patients with chronic respiratory failure: a randomized trial. Respirology 2019;24(12):1204-1211.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1111/resp.13546&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

32. 32.Kelly JL, Jaye J, Pickersgill RE, Chatwin M, Morrell MJ, Simonds AK. Randomized trial of “intelligent” auto-titrating ventilation versus standard pressure support noninvasive ventilation: impact on adherence and physiological outcomes. Respirology 2014;19(4):596-603.
    
    

33. 33.Ferguson KA, Strong MJ, Ahmad D, George CF. Sleep-disordered breathing in amyotrophic lateral sclerosis. Chest 1996;110(3):664-669.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1378/chest.110.3.664&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=8797409&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=A1996VG59000020&link_type=ISI) 

34. 34.Katzberg HD, Selegiman A, Guion L, Yuan N, Cho SC, Katz JS, et al. Effects of noninvasive ventilation on sleep outcomes in amyotrophic lateral sclerosis. J Clin Sleep Med 2013;09(04):345-351.
    
    

35. 35.Vandoorne E, Vrijsen B, Belge C, Testelmans D, Buyse B. Noninvasive ventilation in amyotrophic lateral sclerosis: effects on sleep quality and quality of life. Acta Clin Belg 2016;71(6):389-394.
    
    

36. 36.Nicholson TT, Smith SB, Siddique T, Sufit R, Ajroud-Driss S, Coleman JM 3rd., et al. Respiratory pattern and tidal volumes differ for pressure support and volume-assured pressure support in amyotrophic lateral sclerosis. Ann Am Thorac Soc 2017;14(7):1139-1146.
    
    

37. 37.Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 update. An Official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med 2019;200(8):e70-e88.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1164/rccm.201908-1590ST&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

38. 38.Fitting JW, Paillex R, Hirt L, Aebischer P, Schluep M. Sniff nasal pressure: a sensitive respiratory test to assess progression of amyotrophic lateral sclerosis. Ann Neurol 1999;46(6):887-893.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1002/1531-8249(199912)46:6<887::AID-ANA11>3.0.CO;2-L&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=10589541&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000083997300011&link_type=ISI) 

39. 39.Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Use of sniff nasal inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2005;171(3):269-274.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1164/rccm.200403-314OC&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=15516537&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000226586400013&link_type=ISI) 

40. 40.Kaminska M, Noel F, Petrof BJ. Optimal method for assessment of respiratory muscle strength in neuromuscular disorders using sniff nasal inspiratory pressure (SNIP). PLoS One 2017;12(5):e0177723.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

41. 41.Windisch W, Freidel K, Schucher B, Baumann H, Wiebel M, Matthys H, et al. The Severe Respiratory Insufficiency (SRI) Questionnaire: a specific measure of health-related quality of life in patients receiving home mechanical ventilation. J Clin Epidemiol 2003;56(8):752-759.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1016/S0895-4356(03)00088-X&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=12954467&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 
    
    [Web of Science](http://rc.rcjournal.com/lookup/external-ref?access_num=000185298500008&link_type=ISI) 

42. 42.IBM Corp. Released IBM SPSS Statistics for Macintosh Version 27.0, 2020.
    
    

43. 43.Crescimanno G, Marrone O, Vianello A. Efficacy and comfort of volume-guaranteed pressure support in patients with chronic ventilatory failure of neuromuscular origin. Respirology 2011;16(4):672-679.
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=21355966&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

44. 44.Jackson CE, McVey AL, Rudnicki S, Dimachkie MM, Barohn RJ. Symptom management and end-of-life care in amyotrophic lateral sclerosis. Neurol Clin 2015;33(4):889-908.
    
    

45. 45.Jadcherla SR, Hogan WJ, Shaker R. Physiology and pathophysiology of glottic reflexes and pulmonary aspiration: from neonates to adults. Semin Respir Crit Care Med 2010;31(5):554-560.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.1055/s-0030-1265896&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=20941656&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

46. 46.Gotesman RD, Lalonde E, McKim DA, Bourque PR, Warman-Chardon J, Zwicker J, et al. Laryngospasm in Amyotrophic Lateral Sclerosis. Muscle Nerve 2021.
    
    

47. 47.Gonzalez-Bermejo J, Morelot-Panzini C, Arnol N, Meininger V, Kraoua S, Salachas F, et al. Prognostic value of efficiently correcting nocturnal desaturations after one month of noninvasive ventilation in amyotrophic lateral sclerosis: a retrospective monocenter observational cohort study. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(5-6):373-379.
    
    [CrossRef](http://rc.rcjournal.com/lookup/external-ref?access_num=10.3109/21678421.2013.776086&link_type=DOI) 
    
    [PubMed](http://rc.rcjournal.com/lookup/external-ref?access_num=23527531&link_type=MED&atom=%2Frespcare%2F67%2F9%2F1109.atom) 

48. 48.Georges M, Attali V, Golmard JL, Morélot-Panzini C, Crevier-Buchman L, Collet JM, et al. Reduced survival in patients with ALS with upper-airway obstructive events on noninvasive ventilation. J Neurol Neurosurg Psychiatry 2016;87(10):1045-1050.
    
    [Abstract/FREE Full Text](http://rc.rcjournal.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czoxMDoiODcvMTAvMTA0NSI7czo0OiJhdG9tIjtzOjI0OiIvcmVzcGNhcmUvNjcvOS8xMTA5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==)