Investigation of efficacy of non-invasive lung ventilation at amyotrophic lateral sclerosis in the Russian Federation

Investigation of efficacy of non-invasive lung ventilation at amyotrophic lateral sclerosis in the Russian Federation

G.N. Levitsky (1.2.3), S.L. Babak (4), O.S. Levin (5), V.V. Zverev (1)

1- Russian Charity ALS Foundation (Moscow), 2- SBHI Moscow MP 107, 3- Clinical Diagnostic Center Real Health (Moscow), 4- Department of Pulmonology of A.I. Evdokimov Moscow State Medical-Stomatological University, 5- Department of Neurology, Russian Academy of Postgraduate Education (Moscow)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by impairment of central (CMN) and peripheral motoneurons (PMN), progressing course and inevitable development of terminal respiratory insufficiency (RI) (1). The main method of RI treatment at ALS is noninvasive lung ventilation (NLV).

The main indications to NLV are: 1) clinical symptoms of RI (dyspnea and fatigue at physical load, reduction of cough, impairment of expectoration, sleep disturbances in the form of somnolence, frequent awakening and feeling of dissatisfaction with sleep), 2) signs of chronic pulmonary heart (pulmonary hypertension, pastose feet, verticalization of the electric axis of the heart), 3) respiratory acidosis of venous blood рН <7.3; 4) PaCO2 > 55 mm Hg or 6 kPa based on the data of capnography, 5) nocturnal saturation of SpО2 < 88% for more than 5 min. after oxygen therapy performance with the rate of 2 l/min, 6) maximal inhalation pressure < 60 cm Н2О based on the data of manometry of inhalation and 7) forced vital lung capacity (FVC) < 50% from the expected value based on the data of spirometry, in accordance with the Consensus on indications to NLV at restrictive RI, chronic obstructive lung disease and nocturnal hypoventilation (6). At ALS, ventilation-related respiratory insufficiency develops, that is why from the whole scope of spirometry values, the FVC is regarded as the most important, as a parameter reflecting the volume of air subjected to gas exchange. In accordance with recommendation of NLV administration at nervous-muscle diseases, the therapeutic effect is achieved at NLV performance for 4 hours and more in the supine position with gradual increase of pressure of inhalation and exhalation with the difference of 6 cm of water column. The possibility of the NLV carrying out for 4 hours a day with a positive result is a criterion of NLV compliance. At nervous-muscle diseases, an NLV regimen with the support of spontaneous breathing with feedback on the rate of respiratory movements, designated as the BIPAP/ST (spontaneous timed), is the most adequate (13, 15).

At the same time, other recommendations concerning commencement of the NLV at ALS exist. In the randomized study, it was demonstrated that at the FVC level of 50-60% only 47% of patients with spinal debut of ALS and only 30% of patients with bulbar ALS can become adapted to the NLV (2). It was established that the NLV statistically significantly prolongs the lifespan in the group of patients with spinal but not bulbar ALS debut. Patients with spinal ALS debut managed to survive by 205 days more. (2). The European consensus of the treatment of ALS adheres to the opinion that the NLV should be commenced as soon as the FVC decreases below 80% (3). In the retrospective study of N. Lechtzin et al., it was demonstrated that ALS patients (combined group of spinal and bulbar debut) with the FVC more than 65% lived on the average by 11 months longer than ALS patients received the NLV at the FVC less than 50% (11). However, in one of studies investigating predictors of adaptation to the NLV at ALS, associations with patients’ gender, age and the FVC at the moment of the treatment beginning (a tendency was observed on the last parameter) were not revealed (7). In the other study, it was demonstrated that the lack or insignificant manifestation of bulbar impairments, lesser rate of FVC drop and body mass index decrease are predictors of adaptation, with adaptation to the NLV administration (4 and more hours a day) and lesser rate of FVC drop being lifespan prolongation predictors. (12). The investigation of the order of increase of pressure values of inhalation and exhalation during the NLV use at ALS in 14 patients was conducted. It was demonstrated that in 78% of adapted patients, optimal pressure values of inhalation and exhalation were 19/5 cm of water column, while in 22% of cases the baseline therapeutical level 9/4 cm of water column was an optimal one. In this study, 44% of patients increased pressure one time, 22% - 2 times, and 6% of patients increased pressure 3 and 5 times (both) (8). In different countries, the number of ALS patients using the NLV and having adapted to the procedure varies. In contrast to the study of Gruis K.L. et al. performed in the USA, where 70% of patients became adapted to the NLV, the study of Ristma B.R. et al. conducted in 15 ALS centers in Canada demonstrated that only 18.3% of ALS patients with indications used the NLV, and the majority of patients failed to adapt to this therapy in 70% of centers (7, 14). At the same time, different approaches to the increase of pressure values of inhalation and exhalation exist: some specialists increase only inhalation pressure, while others prefer to augment both pressure values with the difference of 6 cm of water column (8, 15). Opinions regarding the NLV influence on the quality of life of ALS patients show discrepancy. Thus, L.S. Aboussouan et al. observed improvement of the quality of life assessed using the SF-36, while Zamietra K. et al. did not find out any improvement using the scale ALSSQoL-R (2? 16). It is suggested that mechanisms of therapeutical effect of the NLV at ALS is lessening of respiratory load and weariness of respiratory muscles (10, 15).

The actuality of this study devoted to investigation of the NLV use at ALS is caused, first of all, by contradictory data of foreign trials and the lack of such investigations in the RF. However, at the same time, the NLV use at ALS is practiced in the RF, and different specialists recommend various methodological approaches. As it can be seen from the literature observation, investigation of the NLV use at ALS are scarce, and no commonly accepted opinion on indications and terms for NLV commencement, an optimal regimen of pressure increase, predictors of adaptation and lifespan prolongation, as well as NLV influence on the quality of life of ALS patients is elaborated. Different approaches to NLV performance at ALS, differences in the health care systems and compliance of ALS patients lead to dissimilarity in adaptation to the NLV and efficacy of ALS treatment in different countries (2, 3, 8, 11, 13, 14, 16).

Besides, in the RF, NLV devices are not delivered by the state on preferential conditions to ALS patients, and one of the reasons can be related with the lack of scientific basis supporting the efficacy of this method in the domestic practice. NLV devices are expensive, and under condition forcing patients to purchase them on their own, a question about reasonability of the use of devices working in the regimen “S” rises (spontaneous regimen, without feedback on the respiration rate), which are much cheaper than devices working in the regimen “ST”.

The objective of this study was to investigate the efficacy of the NLV at ALS in the RF. Peculiarities of adaptation to the NLV, the duration of ALS patients’ lifespan and their compliance during the NLV use, as well as the influence of the NLV on parameters of spirometry and patients’ quality of life, were studied.

Materials and methods

The study was performed in the period from 2007 to 2012 at the basis of Moscow Municipal Polyclinic № 144 (now a branch № 3 of Moscow Municipal Polyclinic № 107) and the Department of Pulmonology of the A.I. Evdokimov Moscow State Medical-Stomatological University at the basis of Centrosoyuz Hospital (Moscow) at support of the Russian Charity ALS Foundation (OGRN 1067799028241 as of 25.10.2006). 28 ALS patients were enrolled in the study, 13 men and 15 women at the age of 32-72 years old (mean age 56.2± 9.4), from them, 10 patients with bulbar and 16 patients with spinal debuts. The diagnosis ALS was set based on the Revised El-Escorial Criteria of 1998 and electromyographic Lambert criteria (4, 9) taking in consideration results of magnetic resonance imaging (a department of the central nervous system in the debut projection and more rostral department, namely, situated above). All patients were assessed on the scale ALSFRS-R (5). In 15 patients, the disease progression was rapid, and in 13 patients - slow (progression rate more or less 12 scores/month, respectively).

Devices NLV i-Sleep 22 (BREAS, distributed in the RF by C-Instruments Medical) working in the regimen S were used. In 14 cases, the devices were given by the Russian Charity ALS Foundation, and in 14 cases they were purchased by patients on their own. Initially, all the patients were recommended to use the inhalation pressure 9-10 cm of water column, and exhalation pressure 4 cm of water column (difference 6 cm of water column), then, during a month, they were to reach the ability to breath in the supine position for 4 hours, preferably at night. Patients were obliged to present data with recording of the device operation on a flash-card for analysis every month (at that, the mean time of the use per day, total time of application, value of leakage were studied) and increase inhalation pressure and exhalation by 1 cm of water column, as well as come for spirographic examination (device Spirolan, Lana-Medica, RF) one time in 2-3 months (in 2 months at bulbar debut and/or rapid progression, in 3 months at spinal debut and/or slow progression) with determination of the vital lung capacity (VC), FVC, volume of forced exhalation for 1 second (FEV1) and Tiffeneau index (TI), change of device filters monthly and weekly washing of the air duct with water of ambient temperature and soap. At spinal debut, oronasal, and, at bulbar debut, nasal masks were used. For expression of variables, mean values and standard deviations were applied, the statistical analysis was performed using the software pack BIOSTAT (Hungary, 1998), Mann-Whitney criteria and chi-square, results at р<0.05 were considered reliable.


17 ALS patients managed to adapt to the NLV and 11 failed to adapt (they used the NLV less than 4 hours a day). Among those adapted, 7 patients had slowly progressing disease, as well as among unadapted ‒ 6 patients (х2=0.093, р=0.76), these groups did not differ statistically significantly on representativeness of slow progression.

The lifespan of patients adapted to the NLV was significantly longer and reached 35.1±14.2 months in comparison with unadapted – 22.5±9.2 months (р=0.037). At comparison of ALS patients with spinal debut, the lifespan of adapted patients was reliably longer 31.6±10.3 months in comparison with unadapted patients with spinal debut – 16.3±6.1 months (р=0.049) (Figure 1). At comparison of patients with bulbar debut and secondary bulbar impairments from these groups, no reliable differences in the lifespan were revealed (33.3±3.09 and 33.3 ±9.6 months, р>0.06). Patients used inhalation pressure values from 9 to 14 and exhalation from 4 to 9 mm of water column (9.6±1.2 cm of water column – 4.7±1.25 cm of water column). At that, a tendency to the use of higher pressure values of inhalation and exhalation in adapted patients was observed in comparison with the unadapted ones (10±1.34 and 9,5±1.7 cm of water column for inhalation, р=0.086, and 5.05 1.34 and 4.2±0,8 cm of water column for exhalation, р=0.076, respectively). Adapted patients increased pressure 1-2 times in 47% of cases, while unadapted ones – only in 9% of cases (х2= 2.2; р=0.137). The mean time of the NLV use in adapted patients in minutes a day was 389±123, which was reliably longer than this value in unadapted patients - 92±16 (р=0.001). At that, a small subgroup of adapted of patients could have been separated comprising patients that had reached the therapeutical time of respiration 4 hours significantly quicker (39±7.5 days) in comparison with other patients (184±168 days), р=0.004.

The baseline FVC at spirography was higher by 50% in 10 patients adapted to the NLV and lower in 8 unadapted patients with spinal debut (х2=10.2; р=0.001), higher by 65% in 5 patients adapted to the NLV with bulbar debut of ALS and lower by 65% in 3 unadapted people (х2= 4.2; р=0.038).

Observations of spirography in dynamics in ALS patients during the NLV use were sporadic. Thus, in the group of adapted patients, 4 patients were subjected to the repeated spirography. Figure 2 demonstrates increase of the VC and FVC along with FEV1 at the use of NLV for 1 month. Afterwards, under the condition of deadaptation to the NLV, these values decrease in one female patient, and remained stable in another adapted patient. In three remained patients, these values were stable during the year of therapy.


The study has demonstrated that the NLV use in the regimen “S” (spontaneous) prolongs the lifespan in adapted ALS patients as a whole in the group, mainly, at the expense of the subgroup of patients with spinal, but not bulbar debut, which supports the data of Aboussouan et al. (2). The adaptation to the NLV depends directly on the FVC value and corresponds to the value exceeding 50% for patients with spinal debut and 65% for patients with bulbar debut. It specifies the data of N. Lechtzin about the FVC value necessary for prolongation of the lifespan of ALS patients with spinal debut, as this retrospective study was indicative of the lifespan prolongation for ALS patients with the FVC higher than 65% in the group, as a whole (11). During this study, pressure values in the device were increased once by 47% of adapted patients, while in the study of Gruis et al. by 44% (8). We have revealed two types of adaptation to the device, namely gradual in 13 patients (46.2%) (Figure 3) and forced in 4 patients (14.2%) (Figure 4). The reasons for the forced adaptation during approximately a month period were not established: these patients had both spinal and bulbar debuts, both rapid and slow disease progression. Figure 5 demonstrates the lack of adaptation to the device, while figures 6.1 and 6.2 represent gradual deadaptation in patients with bulbar debut and initially ideal adaptation at the FVC higher than 65%. Single observations of spirographic values in dynamics indicate to the possibility of improvement and stabilization of pulmonary volumes at chronic NLV therapy.

The main conclusions from the study results are as follows: the NLV can increase the lifespan of ALS patients predominantly with spinal debut at baseline FVC higher than 50% using more economically available devices working in the regimenе “S”, which corresponds to the latest recommendation of the European consensus on ALS of 2005 on the necessity of the NLV beginning at the FVC less than 80%, but not 50%, unlike recommendations of 1999 (3, 6). In this study, an insufficient number of observations on NLV successfulness at ALS with bulbar debut with the FVC higher than 65% has been received, which does not allow coming to the statistically confirmed conclusion. It is possible that for ALS patients with bulbar debut, successful NLV can be conducted using more powerful devices with inhalation pressure values to 40 cm of water column (for example, VIVO-40, BREAS) under the condition of early placement of tracheostoma allowing elimination of secreta from the trachea preventing from adaptation of ALS patients with bulbar debut to the NLV.


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  12. Lo Coco D, Marchese S, Pesco MC et al. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival.Neurology. 2006 Sep 12;67(5):761-5. Simonds AK. NIV and neuromuscular disease. Eur Respir Mon, 2008, 41, 224–239.

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  16. Zamietra K, Lehman EB, Felgoise SH et al. Non-invasive ventilation and gastrostomy may not impact overall quality of life in patients with ALS.Amyotroph Lateral Scler. 2012 Jan;13(1):55-8.

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