Mechanical insufflation-exsufflation in a large multicenter cohort of people with amyotrophic lateral sclerosis (ALS) - provision, perceived cough deficiency and treatment satisfaction.

Mechanical insufflation-exsufflation in a large multicenter cohort of people with amyotrophic lateral sclerosis (ALS) - provision, perceived cough deficiency and treatment satisfaction. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mechanical insufflation-exsufflation in a large multicenter cohort of people with amyotrophic lateral sclerosis (ALS) - provision, perceived cough deficiency and treatment satisfaction. André Maier, Dagmar Kettemann, Ute Weyen, Torsten Grehl, Peter Caspar Schulte, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4509203/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Mar, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower peak cough flows (PCF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights symptomatic and palliative potential of MI-E therapy for ALS patients. Health sciences/Neurology/Neurological disorders/Motor neuron disease Health sciences/Neurology/Neurological disorders/Neurodegenerative diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction In amyotrophic lateral sclerosis (ALS) loss of voluntary motor function results in weakness of the tongue and pharyngeal muscles and weakness of the costal, diaphragmatic, abdominal, and accessory muscles 1 . The resulting hypoventilation syndrome leads to respiratory failure, which is the major cause of mortality in ALS 2 . While therapeutic strategies include the provision of non-invasive or invasive ventilation, they are often not technically feasible, not tolerated, or not desired 3 . Beyond hypoventilation, respiratory difficulties decreases reflexive and voluntary coughing abilities and leads to a reduction in airway clearance 4 , which may lead to atelectasis, acute respiratory failure, and pneumonia 5 . Moreover, with bulbar symptoms the accumulation of excessive pharyngeal secretions may aggravate an already critical condition and lead to distressing choking symptoms. Treatment includes drug therapy for secretion management 6 and techniques to maintain or improve coughing 7–9 . Mechanical insufflation-exsufflation, an established therapy known as MI-E or “cough assist,” is also increasingly being used and recommended 10 . MI-E is a cough augmentation strategy in which a device gradually inflates the lungs (insufflation), increases the peak cough flow, mobilizes intercostal muscles groups, and reduces atelectasis 11 . The transition to negative pressure (exsufflation) results in a significant clearance of airway mucus 12 . The indication of MI-E is based on objective criteria — most often, peak expiratory flow (PEF) or peak cough flow (PCF). Both values differ with respect to the maximum value to be reached in the measurement, since moderately higher values are usually achieved through a coughing maneuver. However, with reduced expiratory force, an increasing convergence of values is evident 13 , meaning that the ability to cough declines early in the disease course. Although MI-E therapy increases peak flow and this is generally considered predictive of cough efficiency, this surrogate outcome do not fully capture airway clearance and so the benefits of MI-E therapy for ALS patients remains inconclusive 14,15 . However, use of MI-E can reduce morbidity and need for hospitalization 16 and prolongs survival when utilized alongside non-invasive ventilation 17 . Case studies and clinical experience support the recommendation to provide MI-E to ALS patients with reduced expiratory peak flow and cough deficiency 18–20 . Despite the wide application of MI-E therapy, only limited information is available about patients with ALS using MI-E in home care settings 21 . In particular, there is a need to examine the relationship between an objectively measured and perceived cough impairment because this might influence adhearence to cough augmentation therapies like the application of MI-E in routine clinical care. Self-perceived cough capacity of people with ALS is studied only to a limited extent and self-reported values may not match the measured values of PCF 22 . To date, very little systematic data has been collected on the effects of MI-E use in ALS patients as viewed through the lens of patient-reported symptom relief 21,23 . Thus, the aims of the present study are (I) to evaluate the provision rates and causes of failed procurement of MI-E; (II) to determine the frequency of use of MI-E; (III) to analyze subjective cough deficiency in correlation to symptom relief provided by MI-E; and (IV) to identify patients’ satisfaction with MI-E therapy. Material and Methods Study design A prospective multicenter cohort study was conducted at 12 specialized ALS treatment centers in Germany between 07/2018 and 09/2023. This study was conducted in accordance with STROBE criteria 24 . Participants Subjects who met the following criteria were included in this study: an ALS diagnosis following the revised El Escorial criteria 25 , being older than 18 years of age, a newly-given indication of cough deficiency, and having granted informed consent to participate in the Ambulanzpartner Soziotechnologie (APST) research and case management platform 26–28 . Participants with a severe life-limiting disease other than ALS or with a clinically significant cognitive impairment were not eligible for this trial. Ethical approval and consent to participate The study was conducted in accordance with the established guidelines and regulations approved by the Medical Ethics Committee of Charité – Universitätsmedizin Berlin, Germany, under code EA1/219/15. Subjects received information about the study both verbally and in writing. Informed consent was obtained from all subjects. Setting Diagnosing cough deficiency and case management The primary diagnosis of cough deficiency was established by ALS/MND-trained neurologists and experienced nurses in contributing centers through an assessment interview, by measuring peak cough flow (PCF), slow vital capacity (SVC), and by performing a clinical examination. Following consultations and mutual review with the patient based on shared decision-making principles, an ALS/MND-trained neurologist undertook the final medical indication for MI-E. Once these criteria were met, the patient was referred to a tertiary respiratory medicine center or, if home assessment was suitable, to a certified respiratory therapist (CRT) by the case management service provided by APST. The CRT verified cough deficiency by PCF testing initiated MI-E therapy . Patients and their relatives received training in the use of the device, and support, accessory, and supply services were established. Recommendations on the use of MI-E followed the Guidelines for Non-Invasive and Invasive Home Mechanical Ventilation for Treatment of Chronic Respiratory Failure by the German Society of Pneumology and Mechanical Ventilation (DGP) 20 . Provision with a mechanical insufflation-exsufflation (MI-E) In Germany, specialized providers who deal directly with health insurances based on physician prescriptions provided the MI-E devices, service, and training. The choice of MI-E model was left to the discretion of the specialized providers, as long as state-of-the-art technology was used. This involves using new devices or, for cost reasons, devices that have been refurbished from a pool and are in mint condition. Assessment and data capture All coordinated care and supply data was digitally documented by APST as part of the provision of service. Trained and certified nurses performed respiratory examinations. Neurologists, study coordinators, and study assistants documented clinical and demographic data on distinct case report forms for baseline and follow-up visits. Patient-reported outcomes were captured through printed and digital questionnaires, and structured interviews were conducted via APST’s digital research platform. Variables Demographic and clinical data Collected demographic and clinical data included gender, BMI, age at symptom onset, disease duration, and the findings of the self-administered ALS Functional Rating Scale-Revised (ALSFRS-R) 29 . The ALSFRS-R is a clinically validated and widely used diagnostic instrument that assesses the fine and gross motor functions of arms and legs, bulbar functioning and ventilation. It comprises 12 short questions with 5 anchor points (0–4) as response options. The scale ranges from 0 to 48 points, with the bottom end of the scale reflecting low functionality and more pronounced disease severity. A monthly decline in ALSFRS-R points, or delta ALSFRS-R, is indicative of the rate of deterioration and has prognostic significance 30 . Respiratory data Data reflecting three respiratory parameters that are routinely measured in ALS specialty centers were included as part of this study. First, the slow vital capacity (SVC) is a standard measurement in ALS. It can determine the degree of neuromuscular hypoventilation syndrome and has high prognostic value 31,32 . The indication of an MI-E is based on peak cough flow (PCF) in addition to cough weakness. PCF, the second parameter, measures maximal expiratory airflow velocity during a coughing episode and provides predictive value in terms of the patient’s ability to effectively clear their airway of tracheal aspirate during swallowing and salivary secretion 10,22 . Below thresholds of 270 or 240 l/min, respectively, ineffective coughing is known to result in a greater risk of aspiration 20,33 . Blood gas parameters such as oxygen saturation correlate with respiratory functioning in ALS patients and also serve as prognostic markers 34 . Oxygen saturation was the third documented parameter. Assessment methods for these parameters were not specified, and were instead based on standards of care. In most cases, SVC and PCV measurements were taken with hand-held devices, and oxygen saturation was determined with a pulse oximeter. MI-E therapy indication After a patient was given a medical indication for MI-E therapy, APST coordinators recorded whether treatment was initiated. The provision process was followed systematically and reasons for the failure to provide MI-E therapy were recorded. MI-E use The patient survey recorded the frequency of MI-E use, which was delineated as follows: less than once a day, 1 to 2 times per day, 3 to 4 times per day, and more than 4 times per day. Self-assessment of cough deficiency A major objective of this study was to elucidate the subjectivity of reduced cough efficiency in relation to the objective parameter PCF. Patients were asked how difficult it was for them to cough effectively both at the time of indication for MI-E (i.e., before adoption) and after the provision of the device. Responses were registered on a Numerical Rating Scale (NRS) ranging from 0 (no difficulty) to 10 (strongest difficulty). To enhance evaluability, the following groupings were made: 0 = no cough deficiency, 1–3 = mild cough deficiency, 4–6 moderate cough deficiency, 7–10 = severe cough deficiency. Subjective assessment and recommendation of MI-E Following initiation of the therapy, patients were surveyed about MI-E and their level of satisfaction with it. Patients were asked whether the therapy relieved discomfort associated with difficulty coughing effectively, and answers were registered on an NRS with a range of 0 (no relief) to 10 (highest relief). The Net Promoter Score (NPS) was also used to evaluate participants’ attitudes towards the MI-E 35 . Originally developed for customer relationship management, the NPS has become a tool for evaluating medical devices and clinical applications 26,36,37 . For this study, we calculated NPS scores in response to the question: “How likely is it that you would recommend MI-E to another friend or patient with difficulties coughing effectively?”. Based on an 11-point Likert scale ranging from 0 (recommendation absolutely unlikely) to 10 (recommendation highly likely), participants who gave the therapy a 9 or 10 were considered "promoters" (likely to recommend), those who gave it 7 or 8 points were considered "indifferent," and responders who gave the MI-E 6 to 0 points were considered "detractors" (unlikely to recommend). A final score was determined by subtracting the percentage of detractors from the percentage of promoters. In general, a group with a positive NPS is regarded as supportive, and results over 50 are considered excellent 38 . To avoid categorization difficulties, it is also possible to omit the NPS calculus and merely report average values as they correspond to a given recommendation 35 . Statistical Methods Data was analyzed with IBM SPSS Statistics (Version 27.0). If individual data points were missing, total scores reliant on those items were excluded from statistical analysis. Descriptive analyses were conducted to compare frequencies within assessed parameters. Results were expressed as means (± SD) if distribution was normal, and as medians if numerical data was visualized or if distribution was non-Gaussian. Significant differences between the parameters and, respectively, subgroups of nominally scaled data were assessed by applying contingency tables and Chi-square test. Statistically significant differences of paired samples were analyzed by t-tests. The Wilcoxon test was employed to analyze the statistical power of ordinally-scaled data, while metric data were subjected to the t-test. Correlational analysis was performed with Spearman’s Rho because of the ordinal nature of one of the related scales. To discern group differences within nonparametric data, the Mann–Whitney U test was performed on two independent samples. Statistical significance was ascertained with a risk of error of up to 5% (p-value < 0.05). Results Sample characteristics, therapy indication, and reasons for failure of therapy initiation Within the observation period of 62 months (5 years and two months), an indication for MI-E therapy was given to 694 patients who were subsequently included in this study (baseline visit). In 75.9% (n = 527), MI-E therapy was initiated, and a device was provided. A second visit to collect follow-up data was carried out after an average of 6.2 months (SD = 5.7 months). The follow-up visit comprised 70.2% (n = 370) of patients originally treated with MI-E (Fig. 1 ). MI-E therapy was not initiated in a total of 167 patients of the total cohort (24.1%). The main reason for failure to receive MI-E therapy was death of the patient prior to provision (39.5%, n = 66 of 167, Fig. 2 ). Other reasons were patient reluctance, despite having received an indication for MI-E therapy (21.5%, n = 36); medical or practical reasons such as advanced bulbar syndrome, or contraindications such as emphysema, handling, practicality (21.0%, n = 35); and in rare cases, an insurance company rejecting the provision of MI-E therapy (9.6%; n = 16). For 14 patients (8.4%) the initiation of the MI-E therapy was pending at the time of database closure. Demographic data and baseline characteristics The gender distribution (male to female) was 1:1 (49.8% vs. 50.2%), with the study cohort representing a higher proportion of women relative to the general ALS patient population 39 . The age of ALS onset was within the range of prevalence for the general European population of ALS patients (63.7 years, SD 11.1) 40 . There was no significant age difference between men and women, either at symptom onset or at therapy initiation. At the time of MI-E therapy indication, the average disease course was 33.0 months (2.75 years). Across the total cohort, ALS was moderately advanced, with a mean of 31.4 ALSFRS-R points, but the range was considerable (1–46 points). A decrease in the ALSFRS-R respiratory subscale indicated respiratory involvement (10.3 out of 12, SD = 2.4). Across the entire cohort the disease progressed at an average rate of loss of approximately 0.95 points per month. With regard to PCF, the clinical measure that supports the indication for MI-E therapy, 93.9% of patients (n = 561 out of n = 597 with measured PCF) who received the medical indication for the treatment and 93.4% (n = 425 of 455) of those who obtained MI-E were below the established baseline threshold of 270 l/min. An overview of the demographic and clinical characteristics is provided in Table 1 . Table 1 Demographic and clinical characteristics of participants Characteristics Classification Values Sex, n = 695 female, % (n) 50.3 (349) male, % (n) 49.7 (345) Age, n = 694 at onset, years, mean (SD, R) 63.7 (11.1, 29.4–88.8) n = 694 at time of initiation of MI-E, months, mean (SD, R) 66.5 (10.7, 30.7–89.8) n = 580 at time of use of MI-E, years, mean (SD, R) 67.0 (10.7, 32.6–89.8) Disease duration, n = 694 at time of initiation of MI-E, months, mean (median, IQR, R) 33.0 (20.3, 24.8, 1.9-312.3) Disease progression, n = 687 mean (SD, R) 0.95 (0.91, 0.04–9.08) ALSFRS-R total score (max. 48), n = 687 at time of initiation of MI-E therapy, mean (SD, R) 31.4 (7.5, 1–46) ALSFRS-R respiratory sub-scale score (max. 12), n = 687 at time of initiation of MI-E therapy, mean (SD, R) 10.3 (2.4, 0–12) Body Mass Index (BMI), n = 671 kg/m 2 , mean, (SD, R) 24.0 (4.5, 13.5–43.3) Weight, n = 672 kg, mean (SD, R) 69.7 (14.8, 39–134) Peak Cough Flow (PCF), n = 597 l/min, mean (SD, R) 163.0 (89.8, 0-417) Slow Vital Capacity (SVC), n = 631 %, at time of initiation of MI-E therapy, mean (SD, R) 65.1 (23.3, 8-150) Cough deficiency, n = 685 at time of initiation of MI-E therapy (NRS; SD) 6.4 (2.3) Grouping no cough deficiency (NRS = 0), % (n) 3.1 (21) mild cough deficiency (NRS = 1–3), % (n) 10.2 (70) moderate cough deficiency (NRS = 4–6), % (n) 26.4 (181) severe cough deficiency (NRS = 7–10), % (n) 60.3 (413) Abbreviations: n, number of participants; SD, standard deviation; R, range; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale, revised; MI-E, mechanical insufflator-exsufflator; IQR, interquartile range. Patients with failed initiation MI-E therapy Patients who did not receive MI-E treatment (n = 167), the clinical parameters showed a significantly higher rate of disease progression (1.16 vs. 0.89, p < 0.01), a higher clinical deficit (ALSFRS-R 30.2 vs. 31.8, p < 0.05), and a lower PCF (150 vs. 168, p < 0.05). For those patients the age at indication was higher (68.6 vs. 65.8 years, p < 0.01), whereas vital capacity was lower without statistical significance (SVC 62.5 vs. 65.9, p = 0.117). The analysis of patients who died before the initiation of MI-E therapy (n = 66) compared to those who did not receive it for other reasons (n = 87) showed a significantly higher general clinical deficit (27.3 vs. 32.3, p < 0.001), a higher rate of progression (1.73 vs. 0.74, p < 0.001), and lower PCF and SVC (116 vs. 181 and 53.4 vs.69.1, p < 0.001) despite patients in both groups being of a similar age (69.9 vs. 68.8). Subjective baseline cough deficiency, as determined by the NRS, was not significantly different across all groups (MI-E therapy initiated, not initiated, died before initiation: 6.33 vs. 6.46 vs. 6.66). Respiratory and clinical follow-up data Table 2 presents the measured and captured longitudinal outcome data, which were collected at an average interval of 6.2 months (SD 5.7). In particular, it is noticeable that all clinical values showed a significant, albeit expected, progression between the baseline and follow-up visit. BMI, an important prognostic value for survival in ALS, decreased by 0.7 BMI units or 2.9% (p < 0.001). Respiratory parameters of lung functioning (SVC and PCF), which were already significantly below baseline levels, showed decreases of 9% and 14%, respectively, at follow-up visits (p < 0.001). Interestingly, despite not being clinically meaningful enough at the group level, oxygen saturation values were significantly reduced at the time of the follow-up visit (95.6 to 95.0%; p < 0.001). Table 2 Respiratory and clinical characteristics before and after initiation of MI-E therapy. The assessments of the measurements were performed at time of indication for MI-E therapy (baseline survey) and after initiation of MI-E therapy (follow-up survey). Variable Number of patients, n Baseline survey, M (SD) Follow-up survey, M (SD) M difference (SD, 95% CI) p-value a d b ALSFRS-R total score (max. 48) 371 32.1 (7.1) 26.5 (9.0) 5.57 (6.30, 4.92–6.21) < 0.001 0.884 ALSFRS-R respiratory sub-scale score (max. 12) 369 10.3 (2.5) 8.9 (3.5) 1.42 (2.80, 1.14–1.71) < 0.001 0.510 PCF in l/min 186 184.3 (84.9) 160.1 (100.3) 24.29 (95.59, 10.46–38.12) < 0.001 0.254 Cough deficiency 363 6.4 (2.3) 5.7 (2.4) 0.7 (n/a, n/a-n/a) < 0.001 n/a VK in % 196 68.1 (23.3) 55.8 (26.7) 12.25 (17.61, 9.77–14.73) < 0.001 0.539 SpO 2 201 95.6 (2.4) 95.0 (2.6) 0.62 (2.92, 0.21–1.02) < 0.001 0.211 BMI 337 24.2 (4.5) 23.5 (4.5) 0.69 (1.71, 0.51–0.88) < 0.001 0.405 Weight 342 69.9 (15.1) 68.0 (15.3) 1.81 (5.77, 1.20–2.42) < 0.001 0.314 a Mean differences were accessed by t-test or Wilcoxon signed rank test. A p-value < 0.05 was considered as statistically significant. b Effect size was classified as follows: low effect size: d ≥ 0.2, medium effect size: d ≥ 0.5 and high effect size: d ≥ 0.8 (Cohens, 1988). c in months Abbreviations: PCF, Peak Cough Flow; VK, vital capacity; SpO, peripheral oxygen saturation; d, effect size; Cohen´s d; M, mean; SD, standard deviation; n, number of patients Use of MI-E At the time of the follow-up visit, a majority of patients were receiving MI-E therapy 1 to 2 times per day (47.0%, n = 174). However, more than a fifth of patients used the device less than once a day, including as needed (21.6%, n = 80). Still 29.5% (n = 109) reported usage of three to four times per day (supplementary Fig. 1). To enhance comparability, data of patients who used the device ≥ 3 times a day (n = 116) was analyzed alongside those who used it < 3 times a day (n = 254). Patients with higher use frequency had a significantly higher perceived cough deficiency compared to those with a lower frequency of use (NRS: 6.0 vs. 5.0; p = 0.001). With regard to self-reported cough deficiency relief as a result of MI-E therapy, more frequent use related to greater relief (NRS 6 vs. 7; p = 0.002). Self-assessment of cough deficiency Subjective perception of cough deficiency was assessed using the NRS (0–10). With the aforementioned grouping, it is evident that the majority of patients reported severe (NRS = 7–10; 60.3%, n = 413) or moderate cough deficiency (NRS = 4–6; 26.4%, n = 181) (supplementary Fig. 2). The mean score at baseline was 6.4 (SD 2.3; n = 685), which is considered moderate to severe. Among the patients who did not report cough deficiency in their self-assessments, 93.3% (n = 14/15) had a PCF of less than 270 l/min. Conversely, 97.2% of patients who did not present with a formal PCF-value-based indication for MI-E (PCF > 270 l/min) reported cough deficiency (n = 35/36). The overall correlation between experienced and objectively measured cough deficiency is significant (p < 0.001). The correlation coefficient of only 0.25 results from a high scattering, however, indicating a limited correspondence between self-reported and measured deficiency (supplementary Fig. 3). A group analysis based on the self-assessment of the deficit revealed a significant difference in PCF between participants reporting a strong deficit and those reporting a moderate or mild deficit (Fig. 3 ). Such an association cannot be established for no deficit. Overall, the relationship between self-reported and measured deficits is strongest at the higher levels. Self-reported cough deficiency did not depend on differing levels of bulbar involvement, age or gender. At the time of a follow-up visit 6.2 months (SD 5.74) after the initial visit, respondents rated subjective cough deficiency significantly better than they did at baseline (6.2 vs. 5.7 mean scale points, p < 0.001, Fig. 4 ). The correlation between PCF and self-assessed cough deficiency was comparable between the first and the follow-up visit (r = 0.29). Subjective assessment of symptom relief and recommendation of MI-E When asked about the relief provided by MI-E therapy, more than half of all patients reported that it was strong (51.1%, n = 185) and only 8.0% of all respondents reported having received no relief. 40.9% of patients (n = 148) reported minor to medium symptom relief (supplementary Fig. 4). The group that reported higher levels of relief also showed higher daily use. By separation the participants at the median of an NRS of 7 (n = 176 vs. 183), higher baseline levels of cough deficiency were found in patients who reported higher levels of relief (p = 0.02). However, disease progression, duration, severity, age, and respiratory parameters did not differ significantly. Thus, overall satisfaction with MI-E therapy is high. 56.5% strongly recommended the therapy (9 or 10 points). 23.4% were indifferent (7 to 8 points) and 20.1% gave a weak to no recommendation (0 to 6 points). The NPS was + 36.4 (Fig. 5 ). A significant correlation was found between frequency of use and the likelihood of recommendation, meaning more frequent MI-E use increased the likelihood of a recommendation (Fig. 6 ). The relationship between a patient’s subjective relief for cough deficiency and their likelihood of recommending MI-E was also very strong, with a correlation coefficient of 0.6. Groups reporting no relief, minor relief, medium relief and strong relief showed significantly different recommendation and achieved an NPS value of -65.5, -19.2, + 21.3 and + 76.7, respectively (supplementary Fig. 5). Women were more likely to recommend MI-E therapy than men, although not by a significant margin (NPS: +41.6 vs. +30.9; p = 0.057). Age of respondents did not have impact on recommendation rates. Disease severity, as measured by the ALSFRS-R, had a slight but not significant impact on recommendation rates for MI-E therapy (ALSFRS-R groups subdivided by mean value: ≤ 27 vs. > 27: NPS + 33.1 vs. +39.8; p = 0.129). Discussion Sample characteristics, demographic data, and reasons for failure of therapy initiation Among ALS patients with defined cough deficiency, mechanical insufflation-exsufflation therapy (MI-E) is part of standard care in Germany 18 and in many other countries to increase airway clearance and reduce the risk of life-threatening conditions such as pneumonia and acute respiratory insufficiency. Involving 12 centers and 694 patients, this is the largest study to date aimed at investigating the effects of MI-E therapy on people with ALS in a clinical setting. Because of the substantial number of participants, this study was able to reflect a general yet older ALS population at an advanced stage where cough deficiency on average becomes an important therapeutic target. The gender ratio within the cohort presenting with an indication for MI-E is unusual, as men are generally more affected than women (1.5:1). This might be explained by the fact that cohorts of older age from population-based studies (> 65 years) report a nearly equal gender ratio 41 and the cohort is selected by a MI-E indication. The complex interactions between gender, different respiratory involvement of clinical phenotypes, disease progression, and survival 42 may have also shifted the gender distribution. Given that MI-E therapy is usually indicated when reduced cough efficacy occurs in the context of respiratory insufficiency, clinical parameters revealed a study population with a more advanced stage of ALS on average, although with a wide range. To be included in the study, all relevant respiratory parameters as well as the respiratory subscale of the ALSFRS-R and the self-assessment of cough deficiency showed relevant impairment, justifying MI-E therapy. The difference in baseline PCF levels between those who received MI-E treatment and those who died prior to receiving MI-E therapy emphasizes the prognostic value of the metric. Overall, it emerged that provision of MI-E was unsuccessful in nearly a quarter of all cases. ALS-related reasons, including death prior to provision, accounted for around 60% of this figure. The other 40% had to do with individual reasons relating to the patient, the health insurance provider, or the ongoing provision process. In particular, patients who were not provided MI-E had higher rates of progression, were older and had a higher cough deficiency. The correlation was even clearer in patients who died before therapy was initiated. It can therefore be concluded that members of this group should have received the indication earlier in the disease process or that the provision process itself needs to be accelerated. Respiratory and clinical follow-up data Data collection was carried out over two visits with an average interval of 6 months between them. Incomplete clinical data is partly due to the fact that data was recorded during standard procedures. The COVID-19 pandemic in particular led to restrictions in ALS departments regarding the collection of respiratory parameters. As a result, PCF and SVC values were obtained in just over half of follow-up visits. However, the data is sufficient to show that all respiratory parameters decreased significantly with a small to medium effect size. Surprisingly, and although within a marginally acceptable range on average, even standard oximetry showed a significant decline in the cohort. The same applies to the BMI, an important prognostic metric for ALS survival. Although BMI decreased only by 0.7 units, or 2.9%, this represents a 2% reduction in an estimated survival ratio 43 . Longitudinal data shows an increase in respiratory dysfunction, weight loss and loss of general function on the ALSFRS-R — all parameters that indicate ALS progression. Use of MI-E therapy and self-assessment of cough efficiency MI-E use mostly followed a therapeutic recommendation to use the device every day or several times a day, although there is no specific consensus about frequency of use 44 . Almost 22% of patients used the device less than once per day (21.6%, n = 80), which reflects use when needed. These numbers correspond to an earlier analysis, where up to 73% used the device on a daily basis 45 . Previous studies have shown a solid correlation between reported and actual usage based on digitally-retrieved data, and found that frequency of use is related to secretion burden 21 . This indicates that adherence is not compromised if use is based on needs arising from respiratory impairment or the stage of disease, as opposed to a pre-determined frequency. Furthermore, a mandate daily use in stable patients is questioned 46 . At baseline, an overwhelming majority of participants self-reported a cough deficit, with most documenting relatively severe impairment. The strongest relations between self-perception and measured value were in the higher deficit range. However, analysis shows that a threshold value of less than 270 l/min reflects the experienced difficulties of those affected reasonably well, even though some people may notice a deficit even before reaching this value or will underestimate the objective deficit. Yet, a treatment decision should not be based on strict values, but should be considered on an individual basis and maybe even before a patient reaches a PCF of 270 l/min. Interestingly, we found no association between frequency of use and PCF or SVC. Patients with a higher frequency of use show a higher subjective cough deficit but also greater symptomatic relief. From this, it must be concluded that the subjective dimension has a relevant impact on the administration of the therapy. At follow-up visits, contrary to the clinical parameters, which all decreased, the values of self-assessed cough deficits were significantly better. The question gauging a patient’s cough deficit was deliberately phrased in general terms and did not directly address MI-E therapy. It thus remains an open question whether coughing was perceived to be improved as a result of exertion and reduced secretion accumulation or by better clearance following use of the device. Treatment recommendations and perception of MI-E therapy Regarding cough deficit relief, over 90% of patients reported benefits that most users rated as moderate to strong. It should be emphasized that even more than 50% of all patients described strong relief. In contrast to the subjective assessment of cough deficiency, which is associated with greater relief, clinical parameters such as PCF, SVC, and bulbar score had no statistically significant influence on reported relief. The overall recommendation for MI-E? was high. The NPS, which was originally designed for consumer use before it found its way into medicine, shows very good values for all patients. Recommendation measured with the NRS and thus the NPS show a high correlation between frequency of use and cough deficiency relief. Frequent users show excellent NPS and significantly greater subjective benefits from MI-E. Limitations This was designed as an observational study which takes possible bias and confounding factors into account. Objective measurements were routinely gathered by specialized ALS centers, although not via highly standardized procedures. Respiratory parameters were therefore regarded as disease progression indicators and guidance values for treatment decisions. The study did not set out to deduce the effects of direct treatment from respiratory measurements. However, different data sources and examination techniques can lead to bias. In addition, the COVID-19 pandemic led to missing data, and in particular, respiratory one. Individual self-assessment of cough deficit or actual cough strength can be highly subjective and situation-specific. The clinical definition of a cough is complex 47 , and there is certainly no single conception of it. The extent of secretion, pharyngeal obstruction, possible transient infections and psychological factors can all play important roles in the perception of cough efficacy, and may therefore confound assessments. There are hardly any studies on the self-perception of coughing among ALS patients. Coughing itself, e.g., in public, can have negative social connotations 48 , but it is unclear how and when ALS patients perceive insufficient coughing as a problem. Addressing the issue of coughing on its own before providing MI-E has a desirable educational effect, but can lead to bias as the type and amount of information patients receive can vary considerably. Patient selection was based on individual indications for MI-E therapy, actual supply of devices, and willingness to participate in the study. While this is implicative of a selection bias and constitutes a limitation, the sample size of the study is such that the actual impacts of these factors are not all that strong. Certainly, a controlled study that longitudinally considers patients who do not receive MI-E therapy could potentially produce stronger evidence regarding certain measurements of treatment success. Patients who did not receive MI-E did not have their cough efficacy tracked. Given the existing realities of care and the limitations of our approach, this was simply not achievable. With regard to the strength of the results in terms of cough deficiency and MI-E relief, we must differentiate between self-evaluations performed by patients and evaluations made by medical professionals. It was the purpose of this study to focus on subjective experiences, i.e., on the fine interplay between a severe, potentially life-threatening symptom and patients’ personal treatment experiences and opinions, as well as their subsequent willingness to recommend the therapy. Such perceived benefits cannot always be captured by strictly objective measurement techniques. Although definitive medical criteria for diagnosing cough deficiency was applied in this study, the questionnaire used to measure this symptom and levels of relief has not been validated. In fact, we relied upon the subjective reports of patients to assess the effectiveness of the therapy. Further studies are needed to medically define and measure the effects of MI-E and to align those results with subjective experience. Conclusion This multicenter study to evaluate mechanical insufflator-exsufflator therapy use was conducted in a real-world clinical care setting. By looking at provision data, it is evident that the MI-E indication largely applies to the intended therapeutic target group within the required scope. Some patients could not be treated due to possibly avoidable obstacles. In particular, data for a small number of patients suggests that a medical indication should have been given sooner, when the disease was less advanced. To enable earlier intervention, process optimization such as progression-rate based or predictive provisioning should be implemented 49 . In addition, immediate home adaptation may provide time benefits prior to admission to a tertiary respiratory center. Innovative screening approaches could be explored in the future, such as using sensor technology to recording coughing sounds, for example 50 . In summary, this study provides a favorable picture of MI-E therapy and its apparent value to patients. With the use of MI-E, cough deficiency is perceived to be lower. Meanwhile, the more frequently the therapy is used, the greater the cough deficiency relief and the higher the likelihood of recommendation. Further studies are needed to determine the impact on survival and, in patients who are more likely to require palliative treatment, quality of life. Abbreviations MI-E, Mechanical Insufflation-Exsufflation SVC, Slow Vital Capacity PCF, Peak Cough Flow NRS, Numeric Rating Scale NPS, Net Promoter Score ALSFRS-R, ALS functional rating scale - revised Declarations Acknowledgements The authors wish to thank the patients who participated in this study. Competing interests AM has received presentation and consulting fees from Merz Pharma GmbH & Co., KGaA, ITF Pharma GmbH, Zambon GmbH and Roche Pharma AG. TM has received consulting fees from Cytokinetics, GSK and Desitin Arzneimittel GmbH, and has served on scientific advisory boards for Cytokinetics, GSK and TEVA. TM and CM are founders of the internet platform Ambulanzpartner and hold shares in Ambulanzpartner Soziotechnologie APST GmbH. SP has participated on advisory boards of Biogen and has received consulting fees from Biogen. AKR received speaker fees from Amylyx Pharmaceuticals and served on advisory boards for Biogen and Argenx outside of the submitted work. All other authors declare that they have no conflicts of interest. Author contribution AM, SS, and TM designed and conceptualized the study, analyzed and interpreted data, and drafted the intellectual content of the manuscript. 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13:11:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4509203/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4509203/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-91692-8","type":"published","date":"2025-03-01T15:58:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58514586,"identity":"13742630-4a0f-41db-a490-816c21b0b654","added_by":"auto","created_at":"2024-06-17 16:36:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":78258,"visible":true,"origin":"","legend":"\u003cp\u003eSample characteristics of studied cohort. n = number of patients.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/cd2bdee673c5920d09de4b3f.png"},{"id":58514573,"identity":"5df04745-c330-4bac-8e32-17b232aa1ae5","added_by":"auto","created_at":"2024-06-17 16:36:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82180,"visible":true,"origin":"","legend":"\u003cp\u003eRate of, and reasons for, non-initiation of MI-E therapy. n = number of patients.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/c1d12a1e57dea3bae866a613.png"},{"id":58514581,"identity":"5e2e05af-ba9f-44b0-bff9-88133f959ca3","added_by":"auto","created_at":"2024-06-17 16:36:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56588,"visible":true,"origin":"","legend":"\u003cp\u003eCough deficiency in relation to the PCF. Cough deficiency was assessed by the Numerical Rating Scale (NRS) ranging from 0 (no difficulty) to 10 (strongest difficulty). To enhance evaluability, groupings were made as follows: 0 = no cough deficiency, 1-3 = mild cough deficiency, 4-6 moderate cough deficiency, 7-10 = severe cough deficiency. n=596. n=number of patients, PCF=peak cough flow, p=596.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/2781f54bc7c9d7c42fddf77e.png"},{"id":58514585,"identity":"f42c860e-9efa-4659-9277-c07bd7a46c23","added_by":"auto","created_at":"2024-06-17 16:36:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":70707,"visible":true,"origin":"","legend":"\u003cp\u003eSelf-assed cough deficiency before and after initiation of MI-E therapy. Cough deficiency was assessed by the Numerical Rating Scale (NRS) ranging from 0 (no difficulty) to 10 (strongest difficulty). To enhance evaluability, groupings were made as follows: 0 = no cough deficiency, 1-3 = mild cough deficiency, 4-6 moderate cough deficiency, 7-10 = severe cough deficiency. The interval between baseline and follow-up visits was 6.2 months on average (SD=5.7). \u0026nbsp;n=596\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/c605f2f22669cf328c92a734.png"},{"id":58514578,"identity":"ffa69727-f016-4e1c-b2a5-ae671bbf0079","added_by":"auto","created_at":"2024-06-17 16:36:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":55644,"visible":true,"origin":"","legend":"\u003cp\u003eLikelihood of recommending a mechanical insufflation-exsufflation (MI-E). The NPS was used to assess participants’ likelihood of recommending the MI-E. Scores were calculated based on responses to a single question: “How likely is it that you would recommend the MI-E to another friend or patient who is affected with ALS?” Answers ranged between 0 (absolutely unlikely to recommend) and 10 (very likely to recommend). Participants who responded with a score of 9 or 10 were considered “promoters.” Those who gave the therapy a 7 or 8 were classified as “indifferent,” and participants whose rankings were between 0 and 6 were defined as “detractors” (\u003cstrong\u003eA\u003c/strong\u003e). The NPS was calculated by subtracting the percentage of detractors from the percentage of promoters (\u003cstrong\u003eB\u003c/strong\u003e). n=363; n, number of participants\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/a28b646745eb60ed4d4e54a5.png"},{"id":58514583,"identity":"fa9c917a-0114-44ff-aac2-c8d334f6e5f7","added_by":"auto","created_at":"2024-06-17 16:36:15","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":88755,"visible":true,"origin":"","legend":"\u003cp\u003eLikelihood of recommending a mechanical insufflation-exsufflation (MI-E) with respect to frequency of MI-E use. The NPS was used to assess participants’ likelihood of recommending the MI-E. Scores were calculated based on responses to a single question: “How likely is it that you would recommend the MI-E to another friend or patient who is affected with ALS?” Answers ranged between 0 (absolutely unlikely to recommend) and 10 (very likely to recommend). Participants who responded with a score of 9 or 10 were considered “promoters.” Those who gave the therapy a 7 or 8 were classified as “indifferent,” and participants whose rankings were between 0 and 6 were defined as “detractors” (\u003cstrong\u003eA\u003c/strong\u003e). The NPS was calculated by subtracting the percentage of detractors from the percentage of promoters (\u003cstrong\u003eB\u003c/strong\u003e). n=363; n, number of participants\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/938f4152ab2d95a6199fb9ec.png"},{"id":77623249,"identity":"a31de702-5498-4fd9-a844-55762cc51f22","added_by":"auto","created_at":"2025-03-03 16:11:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1758724,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/35c9f35a-e38f-4a3f-9f17-0d8a759a07c0.pdf"},{"id":58514574,"identity":"073ce8e6-c4e5-4d11-b9d3-b5c0b0fc085a","added_by":"auto","created_at":"2024-06-17 16:36:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":305982,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryinformation20240531.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4509203/v1/4d2faebed8babb92e0fd9114.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mechanical insufflation-exsufflation in a large multicenter cohort of people with amyotrophic lateral sclerosis (ALS) - provision, perceived cough deficiency and treatment satisfaction.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn amyotrophic lateral sclerosis (ALS) loss of voluntary motor function results in weakness of the tongue and pharyngeal muscles and weakness of the costal, diaphragmatic, abdominal, and accessory muscles \u003csup\u003e1\u003c/sup\u003e. The resulting hypoventilation syndrome leads to respiratory failure, which is the major cause of mortality in ALS \u003csup\u003e2\u003c/sup\u003e. While therapeutic strategies include the provision of non-invasive or invasive ventilation, they are often not technically feasible, not tolerated, or not desired \u003csup\u003e3\u003c/sup\u003e. Beyond hypoventilation, respiratory difficulties decreases reflexive and voluntary coughing abilities and leads to a reduction in airway clearance \u003csup\u003e4\u003c/sup\u003e, which may lead to atelectasis, acute respiratory failure, and pneumonia \u003csup\u003e5\u003c/sup\u003e. Moreover, with bulbar symptoms the accumulation of excessive pharyngeal secretions may aggravate an already critical condition and lead to distressing choking symptoms. Treatment includes drug therapy for secretion management \u003csup\u003e6\u003c/sup\u003e and techniques to maintain or improve coughing \u003csup\u003e7\u0026ndash;9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMechanical insufflation-exsufflation, an established therapy known as MI-E or \u0026ldquo;cough assist,\u0026rdquo; is also increasingly being used and recommended \u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMI-E is a cough augmentation strategy in which a device gradually inflates the lungs (insufflation), increases the peak cough flow, mobilizes intercostal muscles groups, and reduces atelectasis \u003csup\u003e11\u003c/sup\u003e. The transition to negative pressure (exsufflation) results in a significant clearance of airway mucus \u003csup\u003e12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe indication of MI-E is based on objective criteria \u0026mdash; most often, peak expiratory flow (PEF) or peak cough flow (PCF). Both values differ with respect to the maximum value to be reached in the measurement, since moderately higher values are usually achieved through a coughing maneuver. However, with reduced expiratory force, an increasing convergence of values is evident \u003csup\u003e13\u003c/sup\u003e, meaning that the ability to cough declines early in the disease course. Although MI-E therapy increases peak flow and this is generally considered predictive of cough efficiency, this surrogate outcome do not fully capture airway clearance and so the benefits of MI-E therapy for ALS patients remains inconclusive \u003csup\u003e14,15\u003c/sup\u003e. However, use of MI-E can reduce morbidity and need for hospitalization \u003csup\u003e16\u003c/sup\u003e and prolongs survival when utilized alongside non-invasive ventilation \u003csup\u003e17\u003c/sup\u003e. Case studies and clinical experience support the recommendation to provide MI-E to ALS patients with reduced expiratory peak flow and cough deficiency \u003csup\u003e18\u0026ndash;20\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eDespite the wide application of MI-E therapy, only limited information is available about patients with ALS using MI-E in home care settings \u003csup\u003e21\u003c/sup\u003e. In particular, there is a need to examine the relationship between an objectively measured and perceived cough impairment because this might influence adhearence to cough augmentation therapies like the application of MI-E in routine clinical care. Self-perceived cough capacity of people with ALS is studied only to a limited extent and self-reported values may not match the measured values of PCF \u003csup\u003e22\u003c/sup\u003e. To date, very little systematic data has been collected on the effects of MI-E use in ALS patients as viewed through the lens of patient-reported symptom relief \u003csup\u003e21,23\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThus, the aims of the present study are (I) to evaluate the provision rates and causes of failed procurement of MI-E; (II) to determine the frequency of use of MI-E; (III) to analyze subjective cough deficiency in correlation to symptom relief provided by MI-E; and (IV) to identify patients\u0026rsquo; satisfaction with MI-E therapy.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eA prospective multicenter cohort study was conducted at 12 specialized ALS treatment centers in Germany between 07/2018 and 09/2023. This study was conducted in accordance with STROBE criteria \u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eSubjects who met the following criteria were included in this study: an ALS diagnosis following the revised El Escorial criteria \u003csup\u003e25\u003c/sup\u003e, being older than 18 years of age, a newly-given indication of cough deficiency, and having granted informed consent to participate in the Ambulanzpartner Soziotechnologie (APST) research and case management platform \u003csup\u003e26\u0026ndash;28\u003c/sup\u003e. Participants with a severe life-limiting disease other than ALS or with a clinically significant cognitive impairment were not eligible for this trial.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e \u003cp\u003e The study was conducted in accordance with the established guidelines and regulations approved by the Medical Ethics Committee of Charit\u0026eacute; \u0026ndash; Universit\u0026auml;tsmedizin Berlin, Germany, under code EA1/219/15. Subjects received information about the study both verbally and in writing. Informed consent was obtained from all subjects.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSetting\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eDiagnosing cough deficiency and case management\u003c/h2\u003e \u003cp\u003eThe primary diagnosis of cough deficiency was established by ALS/MND-trained neurologists and experienced nurses in contributing centers through an assessment interview, by measuring peak cough flow (PCF), slow vital capacity (SVC), and by performing a clinical examination. Following consultations and mutual review with the patient based on shared decision-making principles, an ALS/MND-trained neurologist undertook the final medical indication for MI-E.\u003c/p\u003e \u003cp\u003eOnce these criteria were met, the patient was referred to a tertiary respiratory medicine center or, if home assessment was suitable, to a certified respiratory therapist (CRT) by the case management service provided by APST. The CRT verified cough deficiency by PCF testing initiated MI-E therapy\u003c/p\u003e \u003cp\u003e. Patients and their relatives received training in the use of the device, and support, accessory, and supply services were established. Recommendations on the use of MI-E followed the Guidelines for Non-Invasive and Invasive Home Mechanical Ventilation for Treatment of Chronic Respiratory Failure by the German Society of Pneumology and Mechanical Ventilation (DGP) \u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eProvision with a mechanical insufflation-exsufflation (MI-E)\u003c/h2\u003e \u003cp\u003eIn Germany, specialized providers who deal directly with health insurances based on physician prescriptions provided the MI-E devices, service, and training. The choice of MI-E model was left to the discretion of the specialized providers, as long as state-of-the-art technology was used. This involves using new devices or, for cost reasons, devices that have been refurbished from a pool and are in mint condition.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssessment and data capture\u003c/h2\u003e \u003cp\u003eAll coordinated care and supply data was digitally documented by APST as part of the provision of service. Trained and certified nurses performed respiratory examinations. Neurologists, study coordinators, and study assistants documented clinical and demographic data on distinct case report forms for baseline and follow-up visits. Patient-reported outcomes were captured through printed and digital questionnaires, and structured interviews were conducted via APST\u0026rsquo;s digital research platform.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section4\"\u003e \u003ch2\u003eDemographic and clinical data\u003c/h2\u003e \u003cp\u003eCollected demographic and clinical data included gender, BMI, age at symptom onset, disease duration, and the findings of the self-administered ALS Functional Rating Scale-Revised (ALSFRS-R) \u003csup\u003e29\u003c/sup\u003e. The ALSFRS-R is a clinically validated and widely used diagnostic instrument that assesses the fine and gross motor functions of arms and legs, bulbar functioning and ventilation. It comprises 12 short questions with 5 anchor points (0\u0026ndash;4) as response options. The scale ranges from 0 to 48 points, with the bottom end of the scale reflecting low functionality and more pronounced disease severity. A monthly decline in ALSFRS-R points, or delta ALSFRS-R, is indicative of the rate of deterioration and has prognostic significance \u003csup\u003e30\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRespiratory data\u003c/h2\u003e \u003cp\u003eData reflecting three respiratory parameters that are routinely measured in ALS specialty centers were included as part of this study. First, the slow vital capacity (SVC) is a standard measurement in ALS. It can determine the degree of neuromuscular hypoventilation syndrome and has high prognostic value \u003csup\u003e31,32\u003c/sup\u003e. The indication of an MI-E is based on peak cough flow (PCF) in addition to cough weakness. PCF, the second parameter, measures maximal expiratory airflow velocity during a coughing episode and provides predictive value in terms of the patient\u0026rsquo;s ability to effectively clear their airway of tracheal aspirate during swallowing and salivary secretion \u003csup\u003e10,22\u003c/sup\u003e. Below thresholds of 270 or 240 l/min, respectively, ineffective coughing is known to result in a greater risk of aspiration \u003csup\u003e20,33\u003c/sup\u003e. Blood gas parameters such as oxygen saturation correlate with respiratory functioning in ALS patients and also serve as prognostic markers \u003csup\u003e34\u003c/sup\u003e. Oxygen saturation was the third documented parameter.\u003c/p\u003e \u003cp\u003eAssessment methods for these parameters were not specified, and were instead based on standards of care. In most cases, SVC and PCV measurements were taken with hand-held devices, and oxygen saturation was determined with a pulse oximeter.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMI-E therapy indication\u003c/h2\u003e \u003cp\u003eAfter a patient was given a medical indication for MI-E therapy, APST coordinators recorded whether treatment was initiated. The provision process was followed systematically and reasons for the failure to provide MI-E therapy were recorded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMI-E use\u003c/h2\u003e \u003cp\u003eThe patient survey recorded the frequency of MI-E use, which was delineated as follows: less than once a day, 1 to 2 times per day, 3 to 4 times per day, and more than 4 times per day.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSelf-assessment of cough deficiency\u003c/h2\u003e \u003cp\u003eA major objective of this study was to elucidate the subjectivity of reduced cough efficiency in relation to the objective parameter PCF. Patients were asked how difficult it was for them to cough effectively both at the time of indication for MI-E (i.e., before adoption) and after the provision of the device. Responses were registered on a Numerical Rating Scale (NRS) ranging from 0 (no difficulty) to 10 (strongest difficulty). To enhance evaluability, the following groupings were made: 0\u0026thinsp;=\u0026thinsp;no cough deficiency, 1\u0026ndash;3\u0026thinsp;=\u0026thinsp;mild cough deficiency, 4\u0026ndash;6 moderate cough deficiency, 7\u0026ndash;10\u0026thinsp;=\u0026thinsp;severe cough deficiency.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSubjective assessment and recommendation of MI-E\u003c/h2\u003e \u003cp\u003eFollowing initiation of the therapy, patients were surveyed about MI-E and their level of satisfaction with it. Patients were asked whether the therapy relieved discomfort associated with difficulty coughing effectively, and answers were registered on an NRS with a range of 0 (no relief) to 10 (highest relief).\u003c/p\u003e \u003cp\u003eThe Net Promoter Score (NPS) was also used to evaluate participants\u0026rsquo; attitudes towards the MI-E \u003csup\u003e35\u003c/sup\u003e. Originally developed for customer relationship management, the NPS has become a tool for evaluating medical devices and clinical applications \u003csup\u003e26,36,37\u003c/sup\u003e. For this study, we calculated NPS scores in response to the question: \u0026ldquo;How likely is it that you would recommend MI-E to another friend or patient with difficulties coughing effectively?\u0026rdquo;. Based on an 11-point Likert scale ranging from 0 (recommendation absolutely unlikely) to 10 (recommendation highly likely), participants who gave the therapy a 9 or 10 were considered \"promoters\" (likely to recommend), those who gave it 7 or 8 points were considered \"indifferent,\" and responders who gave the MI-E 6 to 0 points were considered \"detractors\" (unlikely to recommend). A final score was determined by subtracting the percentage of detractors from the percentage of promoters. In general, a group with a positive NPS is regarded as supportive, and results over 50 are considered excellent \u003csup\u003e38\u003c/sup\u003e. To avoid categorization difficulties, it is also possible to omit the NPS calculus and merely report average values as they correspond to a given recommendation \u003csup\u003e35\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Methods\u003c/h2\u003e \u003cp\u003eData was analyzed with IBM SPSS Statistics (Version 27.0). If individual data points were missing, total scores reliant on those items were excluded from statistical analysis. Descriptive analyses were conducted to compare frequencies within assessed parameters. Results were expressed as means (\u0026plusmn;\u0026thinsp;SD) if distribution was normal, and as medians if numerical data was visualized or if distribution was non-Gaussian. Significant differences between the parameters and, respectively, subgroups of nominally scaled data were assessed by applying contingency tables and Chi-square test. Statistically significant differences of paired samples were analyzed by t-tests. The Wilcoxon test was employed to analyze the statistical power of ordinally-scaled data, while metric data were subjected to the t-test. Correlational analysis was performed with Spearman\u0026rsquo;s Rho because of the ordinal nature of one of the related scales. To discern group differences within nonparametric data, the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test was performed on two independent samples. Statistical significance was ascertained with a risk of error of up to 5% (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSample characteristics, therapy indication, and reasons for failure of therapy initiation\u003c/h2\u003e \u003cp\u003eWithin the observation period of 62 months (5 years and two months), an indication for MI-E therapy was given to 694 patients who were subsequently included in this study (baseline visit). In 75.9% (n\u0026thinsp;=\u0026thinsp;527), MI-E therapy was initiated, and a device was provided. A second visit to collect follow-up data was carried out after an average of 6.2 months (SD\u0026thinsp;=\u0026thinsp;5.7 months). The follow-up visit comprised 70.2% (n\u0026thinsp;=\u0026thinsp;370) of patients originally treated with MI-E (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMI-E therapy was not initiated in a total of 167 patients of the total cohort (24.1%). The main reason for failure to receive MI-E therapy was death of the patient prior to provision (39.5%, n\u0026thinsp;=\u0026thinsp;66 of 167, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Other reasons were patient reluctance, despite having received an indication for MI-E therapy (21.5%, n\u0026thinsp;=\u0026thinsp;36); medical or practical reasons such as advanced bulbar syndrome, or contraindications such as emphysema, handling, practicality (21.0%, n\u0026thinsp;=\u0026thinsp;35); and in rare cases, an insurance company rejecting the provision of MI-E therapy (9.6%; n\u0026thinsp;=\u0026thinsp;16). For 14 patients (8.4%) the initiation of the MI-E therapy was pending at the time of database closure.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eDemographic data and baseline characteristics\u003c/h2\u003e \u003cp\u003eThe gender distribution (male to female) was 1:1 (49.8% vs. 50.2%), with the study cohort representing a higher proportion of women relative to the general ALS patient population \u003csup\u003e39\u003c/sup\u003e. The age of ALS onset was within the range of prevalence for the general European population of ALS patients (63.7 years, SD 11.1) \u003csup\u003e40\u003c/sup\u003e. There was no significant age difference between men and women, either at symptom onset or at therapy initiation. At the time of MI-E therapy indication, the average disease course was 33.0 months (2.75 years).\u003c/p\u003e \u003cp\u003eAcross the total cohort, ALS was moderately advanced, with a mean of 31.4 ALSFRS-R points, but the range was considerable (1\u0026ndash;46 points). A decrease in the ALSFRS-R respiratory subscale indicated respiratory involvement (10.3 out of 12, SD\u0026thinsp;=\u0026thinsp;2.4). Across the entire cohort the disease progressed at an average rate of loss of approximately 0.95 points per month.\u003c/p\u003e \u003cp\u003eWith regard to PCF, the clinical measure that supports the indication for MI-E therapy, 93.9% of patients (n\u0026thinsp;=\u0026thinsp;561 out of n\u0026thinsp;=\u0026thinsp;597 with measured PCF) who received the medical indication for the treatment and 93.4% (n\u0026thinsp;=\u0026thinsp;425 of 455) of those who obtained MI-E were below the established baseline threshold of 270 l/min.\u003c/p\u003e \u003cp\u003eAn overview of the demographic and clinical characteristics is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClassification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n\u0026thinsp;=\u0026thinsp;695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003efemale, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.3 (349)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emale, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.7 (345)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, n\u0026thinsp;=\u0026thinsp;694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat onset, years, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.7 (11.1, 29.4\u0026ndash;88.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of initiation of MI-E, months, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.5 (10.7, 30.7\u0026ndash;89.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;580\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of use of MI-E, years, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.0 (10.7, 32.6\u0026ndash;89.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, n\u0026thinsp;=\u0026thinsp;694\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of initiation of MI-E, months, mean (median, IQR, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.0 (20.3, 24.8, 1.9-312.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease progression, n\u0026thinsp;=\u0026thinsp;687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.95 (0.91, 0.04\u0026ndash;9.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALSFRS-R total score (max. 48), n\u0026thinsp;=\u0026thinsp;687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of initiation of MI-E therapy, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.4 (7.5, 1\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALSFRS-R respiratory sub-scale score (max. 12), n\u0026thinsp;=\u0026thinsp;687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of initiation of MI-E therapy, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.3 (2.4, 0\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody Mass Index (BMI), n\u0026thinsp;=\u0026thinsp;671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ekg/m\u003csup\u003e2\u003c/sup\u003e, mean, (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0 (4.5, 13.5\u0026ndash;43.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, n\u0026thinsp;=\u0026thinsp;672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ekg, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.7 (14.8, 39\u0026ndash;134)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak Cough Flow (PCF), n\u0026thinsp;=\u0026thinsp;597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003el/min, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163.0 (89.8, 0-417)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow Vital Capacity (SVC), n\u0026thinsp;=\u0026thinsp;631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%, at time of initiation of MI-E therapy, mean (SD, R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.1 (23.3, 8-150)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough deficiency, n\u0026thinsp;=\u0026thinsp;685\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eat time of initiation of MI-E therapy (NRS; SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrouping\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno cough deficiency (NRS\u0026thinsp;=\u0026thinsp;0), % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.1 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emild cough deficiency (NRS\u0026thinsp;=\u0026thinsp;1\u0026ndash;3), % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.2 (70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emoderate cough deficiency (NRS\u0026thinsp;=\u0026thinsp;4\u0026ndash;6), % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.4 (181)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esevere cough deficiency (NRS\u0026thinsp;=\u0026thinsp;7\u0026ndash;10), % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.3 (413)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: n, number of participants; SD, standard deviation; R, range; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale, revised; MI-E, mechanical insufflator-exsufflator; IQR, interquartile range.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003ePatients with failed initiation MI-E therapy\u003c/h2\u003e \u003cp\u003ePatients who did not receive MI-E treatment (n\u0026thinsp;=\u0026thinsp;167), the clinical parameters showed a significantly higher rate of disease progression (1.16 vs. 0.89, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), a higher clinical deficit (ALSFRS-R 30.2 vs. 31.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and a lower PCF (150 vs. 168, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For those patients the age at indication was higher (68.6 vs. 65.8 years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), whereas vital capacity was lower without statistical significance (SVC 62.5 vs. 65.9, p\u0026thinsp;=\u0026thinsp;0.117).\u003c/p\u003e \u003cp\u003eThe analysis of patients who died before the initiation of MI-E therapy (n\u0026thinsp;=\u0026thinsp;66) compared to those who did not receive it for other reasons (n\u0026thinsp;=\u0026thinsp;87) showed a significantly higher general clinical deficit (27.3 vs. 32.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), a higher rate of progression (1.73 vs. 0.74, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and lower PCF and SVC (116 vs. 181 and 53.4 vs.69.1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) despite patients in both groups being of a similar age (69.9 vs. 68.8).\u003c/p\u003e \u003cp\u003eSubjective baseline cough deficiency, as determined by the NRS, was not significantly different across all groups (MI-E therapy initiated, not initiated, died before initiation: 6.33 vs. 6.46 vs. 6.66).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eRespiratory and clinical follow-up data\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the measured and captured longitudinal outcome data, which were collected at an average interval of 6.2 months (SD 5.7). In particular, it is noticeable that all clinical values showed a significant, albeit expected, progression between the baseline and follow-up visit. BMI, an important prognostic value for survival in ALS, decreased by 0.7 BMI units or 2.9% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Respiratory parameters of lung functioning (SVC and PCF), which were already significantly below baseline levels, showed decreases of 9% and 14%, respectively, at follow-up visits (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Interestingly, despite not being clinically meaningful enough at the group level, oxygen saturation values were significantly reduced at the time of the follow-up visit (95.6 to 95.0%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRespiratory and clinical characteristics before and after initiation of MI-E therapy. The assessments of the measurements were performed at time of indication for MI-E therapy (baseline survey) and after initiation of MI-E therapy (follow-up survey).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBaseline survey,\u003c/p\u003e \u003cp\u003eM (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFollow-up survey, M (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM difference (SD, 95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ed\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALSFRS-R total score (max. 48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.5 (9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.57 (6.30, 4.92\u0026ndash;6.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.884\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALSFRS-R respiratory sub-scale score (max. 12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e369\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.3 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.9 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.42 (2.80, 1.14\u0026ndash;1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.510\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCF in l/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184.3 (84.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e160.1 (100.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.29 (95.59, 10.46\u0026ndash;38.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.7 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7 (n/a, n/a-n/a)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVK in %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.1 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55.8 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.25 (17.61, 9.77\u0026ndash;14.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.539\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpO\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95.6 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95.0 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.62 (2.92, 0.21\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.211\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e337\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.2 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.5 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.69 (1.71, 0.51\u0026ndash;0.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.9 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.0 (15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.81 (5.77, 1.20\u0026ndash;2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.314\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Mean differences were accessed by t-test or Wilcoxon signed rank test. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Effect size was classified as follows: low effect size: d\u0026thinsp;\u0026ge;\u0026thinsp;0.2, medium effect size: d \u0026ge;\u0026nbsp;0.5 and high effect size: d\u0026thinsp;\u0026ge;\u0026thinsp;0.8 (Cohens, 1988).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003ec\u003c/sup\u003e in months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: PCF, Peak Cough Flow; VK, vital capacity; SpO, peripheral oxygen saturation; d, effect size; Cohen\u0026acute;s d; M, mean; SD, standard deviation; n, number of patients\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eUse of MI-E\u003c/h2\u003e \u003cp\u003eAt the time of the follow-up visit, a majority of patients were receiving MI-E therapy 1 to 2 times per day (47.0%, n\u0026thinsp;=\u0026thinsp;174). However, more than a fifth of patients used the device less than once a day, including as needed (21.6%, n\u0026thinsp;=\u0026thinsp;80). Still 29.5% (n\u0026thinsp;=\u0026thinsp;109) reported usage of three to four times per day (supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eTo enhance comparability, data of patients who used the device\u0026thinsp;\u0026ge;\u0026thinsp;3 times a day (n\u0026thinsp;=\u0026thinsp;116) was analyzed alongside those who used it \u0026lt;\u0026thinsp;3 times a day (n\u0026thinsp;=\u0026thinsp;254). Patients with higher use frequency had a significantly higher perceived cough deficiency compared to those with a lower frequency of use (NRS: 6.0 vs. 5.0; p\u0026thinsp;=\u0026thinsp;0.001). With regard to self-reported cough deficiency relief as a result of MI-E therapy, more frequent use related to greater relief (NRS 6 vs. 7; p\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eSelf-assessment of cough deficiency\u003c/h2\u003e \u003cp\u003eSubjective perception of cough deficiency was assessed using the NRS (0\u0026ndash;10). With the aforementioned grouping, it is evident that the majority of patients reported severe (NRS\u0026thinsp;=\u0026thinsp;7\u0026ndash;10; 60.3%, n\u0026thinsp;=\u0026thinsp;413) or moderate cough deficiency (NRS\u0026thinsp;=\u0026thinsp;4\u0026ndash;6; 26.4%, n\u0026thinsp;=\u0026thinsp;181) (supplementary Fig.\u0026nbsp;2). The mean score at baseline was 6.4 (SD 2.3; n\u0026thinsp;=\u0026thinsp;685), which is considered moderate to severe.\u003c/p\u003e \u003cp\u003eAmong the patients who did not report cough deficiency in their self-assessments, 93.3% (n\u0026thinsp;=\u0026thinsp;14/15) had a PCF of less than 270 l/min. Conversely, 97.2% of patients who did not present with a formal PCF-value-based indication for MI-E (PCF\u0026thinsp;\u0026gt;\u0026thinsp;270 l/min) reported cough deficiency (n\u0026thinsp;=\u0026thinsp;35/36). The overall correlation between experienced and objectively measured cough deficiency is significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The correlation coefficient of only 0.25 results from a high scattering, however, indicating a limited correspondence between self-reported and measured deficiency (supplementary Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eA group analysis based on the self-assessment of the deficit revealed a significant difference in PCF between participants reporting a strong deficit and those reporting a moderate or mild deficit (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Such an association cannot be established for no deficit. Overall, the relationship between self-reported and measured deficits is strongest at the higher levels. Self-reported cough deficiency did not depend on differing levels of bulbar involvement, age or gender.\u003c/p\u003e \u003cp\u003eAt the time of a follow-up visit 6.2 months (SD 5.74) after the initial visit, respondents rated subjective cough deficiency significantly better than they did at baseline (6.2 vs. 5.7 mean scale points, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The correlation between PCF and self-assessed cough deficiency was comparable between the first and the follow-up visit (r\u0026thinsp;=\u0026thinsp;0.29).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eSubjective assessment of symptom relief and recommendation of MI-E\u003c/h2\u003e \u003cp\u003eWhen asked about the relief provided by MI-E therapy, more than half of all patients reported that it was strong (51.1%, n\u0026thinsp;=\u0026thinsp;185) and only 8.0% of all respondents reported having received no relief. 40.9% of patients (n\u0026thinsp;=\u0026thinsp;148) reported minor to medium symptom relief (supplementary Fig.\u0026nbsp;4). The group that reported higher levels of relief also showed higher daily use. By separation the participants at the median of an NRS of 7 (n\u0026thinsp;=\u0026thinsp;176 vs. 183), higher baseline levels of cough deficiency were found in patients who reported higher levels of relief (p\u0026thinsp;=\u0026thinsp;0.02). However, disease progression, duration, severity, age, and respiratory parameters did not differ significantly.\u003c/p\u003e \u003cp\u003eThus, overall satisfaction with MI-E therapy is high. 56.5% strongly recommended the therapy (9 or 10 points). 23.4% were indifferent (7 to 8 points) and 20.1% gave a weak to no recommendation (0 to 6 points). The NPS was +\u0026thinsp;36.4 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). A significant correlation was found between frequency of use and the likelihood of recommendation, meaning more frequent MI-E use increased the likelihood of a recommendation (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe relationship between a patient\u0026rsquo;s subjective relief for cough deficiency and their likelihood of recommending MI-E was also very strong, with a correlation coefficient of 0.6. Groups reporting no relief, minor relief, medium relief and strong relief showed significantly different recommendation and achieved an NPS value of -65.5, -19.2, +\u0026thinsp;21.3 and +\u0026thinsp;76.7, respectively (supplementary Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003eWomen were more likely to recommend MI-E therapy than men, although not by a significant margin (NPS: +41.6 vs. +30.9; p\u0026thinsp;=\u0026thinsp;0.057). Age of respondents did not have impact on recommendation rates. Disease severity, as measured by the ALSFRS-R, had a slight but not significant impact on recommendation rates for MI-E therapy (ALSFRS-R groups subdivided by mean value: \u0026le; 27 vs. \u0026gt; 27: NPS\u0026thinsp;+\u0026thinsp;33.1 vs. +39.8; p\u0026thinsp;=\u0026thinsp;0.129).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003eSample characteristics, demographic data, and reasons for failure of therapy initiation\u003c/h2\u003e \u003cp\u003eAmong ALS patients with defined cough deficiency, mechanical insufflation-exsufflation therapy (MI-E) is part of standard care in Germany \u003csup\u003e18\u003c/sup\u003e and in many other countries to increase airway clearance and reduce the risk of life-threatening conditions such as pneumonia and acute respiratory insufficiency.\u003c/p\u003e \u003cp\u003eInvolving 12 centers and 694 patients, this is the largest study to date aimed at investigating the effects of MI-E therapy on people with ALS in a clinical setting. Because of the substantial number of participants, this study was able to reflect a general yet older ALS population at an advanced stage where cough deficiency on average becomes an important therapeutic target.\u003c/p\u003e \u003cp\u003eThe gender ratio within the cohort presenting with an indication for MI-E is unusual, as men are generally more affected than women (1.5:1). This might be explained by the fact that cohorts of older age from population-based studies (\u0026gt;\u0026thinsp;65 years) report a nearly equal gender ratio \u003csup\u003e41\u003c/sup\u003e and the cohort is selected by a MI-E indication. The complex interactions between gender, different respiratory involvement of clinical phenotypes, disease progression, and survival \u003csup\u003e42\u003c/sup\u003e may have also shifted the gender distribution.\u003c/p\u003e \u003cp\u003eGiven that MI-E therapy is usually indicated when reduced cough efficacy occurs in the context of respiratory insufficiency, clinical parameters revealed a study population with a more advanced stage of ALS on average, although with a wide range. To be included in the study, all relevant respiratory parameters as well as the respiratory subscale of the ALSFRS-R and the self-assessment of cough deficiency showed relevant impairment, justifying MI-E therapy. The difference in baseline PCF levels between those who received MI-E treatment and those who died prior to receiving MI-E therapy emphasizes the prognostic value of the metric. Overall, it emerged that provision of MI-E was unsuccessful in nearly a quarter of all cases. ALS-related reasons, including death prior to provision, accounted for around 60% of this figure. The other 40% had to do with individual reasons relating to the patient, the health insurance provider, or the ongoing provision process.\u003c/p\u003e \u003cp\u003eIn particular, patients who were not provided MI-E had higher rates of progression, were older and had a higher cough deficiency. The correlation was even clearer in patients who died before therapy was initiated. It can therefore be concluded that members of this group should have received the indication earlier in the disease process or that the provision process itself needs to be accelerated.\u003c/p\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eRespiratory and clinical follow-up data\u003c/h2\u003e \u003cp\u003eData collection was carried out over two visits with an average interval of 6 months between them. Incomplete clinical data is partly due to the fact that data was recorded during standard procedures. The COVID-19 pandemic in particular led to restrictions in ALS departments regarding the collection of respiratory parameters. As a result, PCF and SVC values were obtained in just over half of follow-up visits. However, the data is sufficient to show that all respiratory parameters decreased significantly with a small to medium effect size. Surprisingly, and although within a marginally acceptable range on average, even standard oximetry showed a significant decline in the cohort. The same applies to the BMI, an important prognostic metric for ALS survival. Although BMI decreased only by 0.7 units, or 2.9%, this represents a 2% reduction in an estimated survival ratio \u003csup\u003e43\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLongitudinal data shows an increase in respiratory dysfunction, weight loss and loss of general function on the ALSFRS-R \u0026mdash; all parameters that indicate ALS progression.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eUse of MI-E therapy and self-assessment of cough efficiency\u003c/h2\u003e \u003cp\u003eMI-E use mostly followed a therapeutic recommendation to use the device every day or several times a day, although there is no specific consensus about frequency of use \u003csup\u003e44\u003c/sup\u003e. Almost 22% of patients used the device less than once per day (21.6%, n\u0026thinsp;=\u0026thinsp;80), which reflects use when needed. These numbers correspond to an earlier analysis, where up to 73% used the device on a daily basis \u003csup\u003e45\u003c/sup\u003e. Previous studies have shown a solid correlation between reported and actual usage based on digitally-retrieved data, and found that frequency of use is related to secretion burden \u003csup\u003e21\u003c/sup\u003e. This indicates that adherence is not compromised if use is based on needs arising from respiratory impairment or the stage of disease, as opposed to a pre-determined frequency. Furthermore, a mandate daily use in stable patients is questioned \u003csup\u003e46\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e At baseline, an overwhelming majority of participants self-reported a cough deficit, with most documenting relatively severe impairment. The strongest relations between self-perception and measured value were in the higher deficit range. However, analysis shows that a threshold value of less than 270 l/min reflects the experienced difficulties of those affected reasonably well, even though some people may notice a deficit even before reaching this value or will underestimate the objective deficit. Yet, a treatment decision should not be based on strict values, but should be considered on an individual basis and maybe even before a patient reaches a PCF of 270 l/min. Interestingly, we found no association between frequency of use and PCF or SVC. Patients with a higher frequency of use show a higher subjective cough deficit but also greater symptomatic relief. From this, it must be concluded that the subjective dimension has a relevant impact on the administration of the therapy.\u003c/p\u003e \u003cp\u003eAt follow-up visits, contrary to the clinical parameters, which all decreased, the values of self-assessed cough deficits were significantly better. The question gauging a patient\u0026rsquo;s cough deficit was deliberately phrased in general terms and did not directly address MI-E therapy. It thus remains an open question whether coughing was perceived to be improved as a result of exertion and reduced secretion accumulation or by better clearance following use of the device.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eTreatment recommendations and perception of MI-E therapy\u003c/h2\u003e \u003cp\u003eRegarding cough deficit relief, over 90% of patients reported benefits that most users rated as moderate to strong. It should be emphasized that even more than 50% of all patients described strong relief. In contrast to the subjective assessment of cough deficiency, which is associated with greater relief, clinical parameters such as PCF, SVC, and bulbar score had no statistically significant influence on reported relief.\u003c/p\u003e \u003cp\u003eThe overall recommendation for MI-E? was high. The NPS, which was originally designed for consumer use before it found its way into medicine, shows very good values for all patients. Recommendation measured with the NRS and thus the NPS show a high correlation between frequency of use and cough deficiency relief. Frequent users show excellent NPS and significantly greater subjective benefits from MI-E.\u003c/p\u003e \u003c/div\u003e"},{"header":"Limitations","content":"\u003cp\u003eThis was designed as an observational study which takes possible bias and confounding factors into account. Objective measurements were routinely gathered by specialized ALS centers, although not via highly standardized procedures. Respiratory parameters were therefore regarded as disease progression indicators and guidance values for treatment decisions. The study did not set out to deduce the effects of direct treatment from respiratory measurements. However, different data sources and examination techniques can lead to bias. In addition, the COVID-19 pandemic led to missing data, and in particular, respiratory one.\u003c/p\u003e \u003cp\u003eIndividual self-assessment of cough deficit or actual cough strength can be highly subjective and situation-specific. The clinical definition of a cough is complex \u003csup\u003e47\u003c/sup\u003e, and there is certainly no single conception of it. The extent of secretion, pharyngeal obstruction, possible transient infections and psychological factors can all play important roles in the perception of cough efficacy, and may therefore confound assessments.\u003c/p\u003e \u003cp\u003eThere are hardly any studies on the self-perception of coughing among ALS patients. Coughing itself, e.g., in public, can have negative social connotations \u003csup\u003e48\u003c/sup\u003e, but it is unclear how and when ALS patients perceive insufficient coughing as a problem. Addressing the issue of coughing on its own before providing MI-E has a desirable educational effect, but can lead to bias as the type and amount of information patients receive can vary considerably.\u003c/p\u003e \u003cp\u003ePatient selection was based on individual indications for MI-E therapy, actual supply of devices, and willingness to participate in the study. While this is implicative of a selection bias and constitutes a limitation, the sample size of the study is such that the actual impacts of these factors are not all that strong.\u003c/p\u003e \u003cp\u003eCertainly, a controlled study that longitudinally considers patients who do not receive MI-E therapy could potentially produce stronger evidence regarding certain measurements of treatment success. Patients who did not receive MI-E did not have their cough efficacy tracked. Given the existing realities of care and the limitations of our approach, this was simply not achievable.\u003c/p\u003e \u003cp\u003eWith regard to the strength of the results in terms of cough deficiency and MI-E relief, we must differentiate between self-evaluations performed by patients and evaluations made by medical professionals.\u003c/p\u003e \u003cp\u003eIt was the purpose of this study to focus on subjective experiences, i.e., on the fine interplay between a severe, potentially life-threatening symptom and patients\u0026rsquo; personal treatment experiences and opinions, as well as their subsequent willingness to recommend the therapy. Such perceived benefits cannot always be captured by strictly objective measurement techniques.\u003c/p\u003e \u003cp\u003eAlthough definitive medical criteria for diagnosing cough deficiency was applied in this study, the questionnaire used to measure this symptom and levels of relief has not been validated. In fact, we relied upon the subjective reports of patients to assess the effectiveness of the therapy. Further studies are needed to medically define and measure the effects of MI-E and to align those results with subjective experience.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis multicenter study to evaluate mechanical insufflator-exsufflator therapy use was conducted in a real-world clinical care setting. By looking at provision data, it is evident that the MI-E indication largely applies to the intended therapeutic target group within the required scope. Some patients could not be treated due to possibly avoidable obstacles. In particular, data for a small number of patients suggests that a medical indication should have been given sooner, when the disease was less advanced. To enable earlier intervention, process optimization such as progression-rate based or predictive provisioning should be implemented \u003csup\u003e49\u003c/sup\u003e. In addition, immediate home adaptation may provide time benefits prior to admission to a tertiary respiratory center. Innovative screening approaches could be explored in the future, such as using sensor technology to recording coughing sounds, for example \u003csup\u003e50\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn summary, this study provides a favorable picture of MI-E therapy and its apparent value to patients. With the use of MI-E, cough deficiency is perceived to be lower. Meanwhile, the more frequently the therapy is used, the greater the cough deficiency relief and the higher the likelihood of recommendation. Further studies are needed to determine the impact on survival and, in patients who are more likely to require palliative treatment, quality of life.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMI-E, Mechanical Insufflation-Exsufflation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSVC, Slow Vital Capacity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCF, Peak Cough Flow\u003c/p\u003e\n\u003cp\u003eNRS, Numeric Rating Scale\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNPS, Net Promoter Score\u003c/p\u003e\n\u003cp\u003eALSFRS-R, ALS functional rating scale - revised\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors wish to thank the patients who participated in this study.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eAM has received presentation and consulting fees from Merz Pharma GmbH \u0026amp; Co., KGaA, ITF Pharma GmbH, Zambon GmbH and Roche Pharma AG. TM has received consulting fees from Cytokinetics, GSK and Desitin Arzneimittel GmbH, and has served on scientific advisory boards for Cytokinetics, GSK and TEVA. TM and CM are founders of the internet platform Ambulanzpartner and hold shares in Ambulanzpartner Soziotechnologie APST GmbH. SP has participated on advisory boards of Biogen and has received consulting fees from Biogen. AKR received speaker fees from Amylyx Pharmaceuticals and served on advisory boards for Biogen and Argenx outside of the submitted work. All other authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eAM, SS, and TM designed and conceptualized the study, analyzed and interpreted data, and drafted the intellectual content of the manuscript. DK played a major role in acquiring and interpreting the data, and in revising the manuscript for intellectual content. UW, TG, CS, RS, AKR, PW, SP, JW JG, JCK, JHW, SR, JN, PK,\u0026nbsp;BK, BH, TH,\u0026nbsp;PS,\u0026nbsp;and CM were responsible for on-site study implementation, participant enrolment, data acquisition, and critically revising the manuscript. BW and AR contributed by collecting preparing, and analyzing data.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eData for this study was provided by Ambulanzpartner Soziotechnologie APST GmbH. However, because this data was used under license, it is not publicly available. It can be obtained from the author Susanne Spittel ([email protected]) upon reasonable request and with the permission of Ambulanzpartner Soziotechnologie APST GmbH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by a research grant from L\u0026ouml;wenstein Medical SE \u0026amp; Co. KG, ResMed Germany Inc. and Jochum Medizintechnik GmbH to APST.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e1. De Carvalho, M., Swash, M. \u0026amp; Pinto, S. Diaphragmatic Neurophysiology and Respiratory Markers in ALS. \u003cem\u003eFront. Neurol.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e, 143 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e2. Kiernan, M. C. \u003cem\u003eet al.\u003c/em\u003e Amyotrophic lateral sclerosis. \u003cem\u003eThe Lancet\u003c/em\u003e \u003cb\u003e377\u003c/b\u003e, 942\u0026ndash;955 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e3. Niedermeyer, S., Murn, M. \u0026amp; Choi, P. J. Respiratory Failure in Amyotrophic Lateral Sclerosis. \u003cem\u003eChest\u003c/em\u003e \u003cb\u003e155\u003c/b\u003e, 401\u0026ndash;408 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e4. Tabor-Gray, L. 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Rep.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 8461 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4509203/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4509203/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n\u0026thinsp;=\u0026thinsp;66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower peak cough flows (PCF) at the time of MI-E indication (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Most patients who received MI-E used it daily (n\u0026thinsp;=\u0026thinsp;290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights symptomatic and palliative potential of MI-E therapy for ALS patients.\u003c/p\u003e","manuscriptTitle":"Mechanical insufflation-exsufflation in a large multicenter cohort of people with amyotrophic lateral sclerosis (ALS) - provision, perceived cough deficiency and treatment satisfaction.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-17 16:36:08","doi":"10.21203/rs.3.rs-4509203/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-12T05:26:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-09T14:35:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-30T15:15:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21350673674912789641503835902915038065","date":"2024-11-21T07:11:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208319444873870630135585975533858495396","date":"2024-11-20T09:59:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-16T08:39:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-03T10:45:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-31T13:35:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-31T13:33:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-31T13:10:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa7f6f1e-9a74-4cf9-9a63-bc75d03d44b0","owner":[],"postedDate":"June 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33053579,"name":"Health sciences/Neurology/Neurological disorders/Motor neuron disease"},{"id":33053580,"name":"Health sciences/Neurology/Neurological disorders/Neurodegenerative diseases"}],"tags":[],"updatedAt":"2025-03-03T16:08:54+00:00","versionOfRecord":{"articleIdentity":"rs-4509203","link":"https://doi.org/10.1038/s41598-025-91692-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-03-01 15:58:13","publishedOnDateReadable":"March 1st, 2025"},"versionCreatedAt":"2024-06-17 16:36:08","video":"","vorDoi":"10.1038/s41598-025-91692-8","vorDoiUrl":"https://doi.org/10.1038/s41598-025-91692-8","workflowStages":[]},"version":"v1","identity":"rs-4509203","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4509203","identity":"rs-4509203","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}