- Email: [email protected]
Assisted vital capacity to assess recruitment level in neuromuscular diseases
Accepted Manuscript Title: Assisted Vital Capacity to Assess Recruitment Level in Neuromuscular Diseases Authors: Dante B Santos, Aur´elien Bor´e, Lorena Del Amo Castrillo, Matthieu Lacombe, Line Falaize, David Orlikowski, Fr´ed´eric Lofaso, H´el`ene Prigent PII: DOI: Reference:
S1569-9048(17)30145-3 http://dx.doi.org/doi:10.1016/j.resp.2017.05.001 RESPNB 2807
To appear in:
Respiratory Physiology & Neurobiology
Received date: Revised date: Accepted date:
28-12-2015 27-4-2017 4-5-2017
Please cite this article as: Santos, Dante B, Bor´e, Aur´elien, Castrillo, Lorena Del Amo, Lacombe, Matthieu, Falaize, Line, Orlikowski, David, Lofaso, Fr´ed´eric, Prigent, H´el`ene, Assisted Vital Capacity to Assess Recruitment Level in Neuromuscular Diseases.Respiratory Physiology and Neurobiology http://dx.doi.org/10.1016/j.resp.2017.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Assisted Vital Capacity to Assess Recruitment Level in Neuromuscular Diseases Dante B Santos PT, PhD;a,b Aurélien Boré, PT;c Lorena Del Amo Castrillo, PT;c Matthieu Lacombe, PT;c Line Falaize;d David Orlikowski MD, PhD;c,d Frédéric Lofaso, MD, PhD;a,e Hélène Prigent MD, PhDa,e a. INSERM U 1179 - Université de Versailles Saint Quentin en Yvelines, UFR des sciences de la Santé Bâtiment Simone Veil 2 avenue de la source de la Bièvre, 78 180 Montigny-leBretonneux, France b. Centro de Fisioterapia e Reabilitação – Hospital Universitário de Brasília, Universidade de Brasília, Brasília-Distrito Federal, Brasilia, Brazil c. Service de Réanimation Médicale, APHP - Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France d. CIC 1429 – INSERM - APHP, Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France e. Physiologie - Explorations Fonctionnelles, APHP, Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France Postal Address Mr Dante Brasil Santos : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Mr Aurélien Boré : [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Ms Lorena Del Amo Castrillo: [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Mr Matthieu Lacombe : [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Ms Line Falaize : [email protected] CIC 1429 – INSERM - APHP, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Pr David Orlikowski : [email protected] CIC 1429 – INSERM - APHP, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France
Pr Frédéric Lofaso : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Dr Hélène Prigent : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Corresponding Author Dr Hélène Prigent Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Phone number : 33-1-7107940 Fax number : 33-1-47107943 E-mail: [email protected] HighlightsNeuromuscular disease may induce respiratory muscle weakness and reduced volumes Improvement of spirometry volumes with mechanical In-Exsufflation was assessed A ±40cmH2O mechanical assistance may normalize reduced respiratory volumes Improvement is greatest in patients with late-onset neuromuscular disease
Abstract Respiratory muscle weakness and chest wall abnormalities in neuromuscular diseases (NMD) may lead to decreased pulmonary volumes. We assessed the reversibility of vital capacity (VC) reduction with mechanical In-Exsufflation (MI-E). We evaluated the effects of positive inspiratory and negative expiratory pressures on spirometric variables under passive (without patients’ participation) and active (with active participation) application in 47 NMD patients. VC, inspiratory capacity (IC), expiratory reserve volume (ERV) were measured during maneuvers without and with MI-E assistance, delivering inspiratory assistance (+40cmH2O), expiratory assistance (-40cmH2O) and both (+/40cmH2O). Passive and active assistance improved significantly VC and IC compared to baseline (P<0.0001 for both). ERV improved only with active assistance which normalized VC in 10, IC in 18 and ERV in 6 patients, mainly in patients with late-onset NMD. MI-E assistance produced greater increases in IC than in ERV, resulting in a VC increase enhanced by patients’ active participation. This type of evaluation may help to evaluate the potential reversibility of restrictive ventilatory pattern in NMDs .
Abbreviations: F: female; M: male; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Keywords: Neuromuscular disorders. Lung volume measurements. Mechanical insufflationexsufflation. Noninvasive respiratory aids; Vital capacity; Volume recruitment.
1.
INTRODUCTION
Overtime, increased morbidity and mortality in neuromuscular diseases (NMDs) is mainly due to impaired respiratory function (Phillips et al., 2001). These diseases are heterogeneous in their evolution, especially in the mechanism and severity of respiratory involvement. It is usually characterized by a restrictive ventilatory pattern caused initially by factors such as respiratory muscle weakness (Phillips et al., 2001) and subsequently also by alterations in the mechanical properties of the respiratory system (Allen, 2010; Perrin et al., 2004). Respiratory muscle weakness leads also to a chronic decrease in chest-wall motion that reflects connective-tissue stiffening and is exacerbated by structural chest-wall abnormalities (Misuri et al., 2000; Perrin et al., 2004). Moreover, atelectasis and chronic decrease in tidal volume (VT) may decrease lung compliance (Estenne et al., 1993; Romei et al., 2012). These mechanical alterations increase the load on weakened respiratory muscles, thereby creating a vicious circle of respiratory dysfunction (Perrin et al., 2004). Permanent chest-wall and lungtissue changes decrease the ability of respiratory-muscle strength improvements to restore a normal vital capacity (VC). Biomechanical and physical considerations suggest that the forces required to overcome the flow-resistive, inertial, and elastic properties of the respiratory system can be produced by the respiratory muscles (e.g., during conventional spirometry maneuvers), by passive in-exsufflation (Welch et al., 1980), or by a combination of both (e.g., during conventional spirometry maneuvers assisted by in-exsufflation) (Fauroux et al., 2008; Sancho et al., 2004). To counterbalance the deleterious effects observed in NMDs, lung recruitment maneuvers have been used to preserve the elasticity of respiratory system (Welch et al., 1980). These recruitment maneuvers can be obtained, for example, by the use of a Mechanical InExsufflation (MI-E) device, which promotes an inspiratory assistance by the delivery of positive pressure, and an expiratory assistance by the creation of negative pressure. Information on the elastic behavior of the respiratory system of NMDs would be useful and the use of MIE, while the patients let themselves be passively insufflated and exsufflated by the device, may allow to indirectly appreciate the elastic properties of the respiratory system, by assessing the
improvement in spirometric volumes. The active participation of the patients during the use of MI-E could in turn help to determine the support necessary to normalize lung volumes and capacities. Highlighting this potential reversibility of lung volumes reduction could identify whether an increase of lung volumes could be expected in case of respiratory muscle strength improvement or if underlying modifications of the elastic properties of the respiratory system would prevent any amelioration in that situation. Thus, by delivering positive pressure insufflation, it is possible to enhance the inspiratory capacity (IC), and likewise providing negative pressure exsufflation is liable to enhance the expiratory reserve volume (Sancho et al., 2004), improving then vital capacity by gains in IC and/or also in ERV. We aimed to assess the ability of NMDs patients to normalize their lung volumes when provided additional noninvasive support by MI-E assistance. In this situation, MI-E acts as a substitute for the effects of respiratory muscles (Azarian et al., 1993). Therefore we evaluated the potential reversibility of spirometric variables and capacities reduction by the delivery of a positive inspiratory pressure and negative expiratory pressure provided by MI-E, during both passive condition (while the patients let themselves be passively insufflated and exsufflated by the device) and active condition (while the patients actively participate to the insufflation an exsufflation maneuvers during slow VC maneuvers), in NMDs patients.
2. METHODS The study was performed between May 2013 and October 2014 at the home ventilation unit of the medical intensive care unit of the Raymond Poincaré Teaching Hospital (Garches, France), after being approved by the ethics committee (CPP IDF 11 – SaintGermain-en-Laye, France, Number2013-A00218-37) and registered on ClinicalTrials.gov. (Number 02022072). 2.1 Participants Adult patients with NMDs and a respiratory involvement defined as VC values lower than 80% of predicted (Quanjer et al., 1993) were solicited during their routine follow-up visits at the unit. Patients with tracheostomy and/or pulmonary disease contraindicating
hyperinsufflation and the use of a MI-E device were excluded. Written informed consent was collected from each patient. As the study aimed to test the ability of pressure support to reverse completely respiratory volume decrease, there was not enough data in the literature to perform a power calculation. In order to explore as many NMDs as possible for this pilot study, we wanted to analyze 50 patients and, therefore, decided to include 55 patients in order to take into account the risk of withdrawal during protocol in this fragile population. 2.2. Initial evaluation At this time, spirometry variables, lung volumes, Maximal static inspiratory (MIP) and expiratory (MEP) pressures were measured using a Vmax 229 SensorMedics System (Yorba Linda, CA, USA) according to standard guidelines (Quanjer et al., 1993) using a flanged mouthpiece and a noseclip. MIP and MEP were measured at FRC and TLC, respectively. Peak cough flow (PCF) was measured using a facemask of appropriate size (Laerdal Medical, Limonest, France) instead of a mouthpiece; it was placed around the mouth to allow mouth opening and reduce cheek compliance. Great care was taken to avoid leaks during the maneuvers. 2.3. Protocol maneuvers (Figure 1) The patients were initially asked to breathe normally while seated comfortably and quietly for 2 minutes, during which respiratory rate and tidal volume were recorded. After these measures, three slow unassisted VC maneuvers were performed (baseline maneuvers). If values differed by more than 5% from the best value, further maneuvers were performed (Quanjer et al., 1993). The protocol of assistance by MI-E device was divided in passive and active assistances. MI-E assistance was always started at the end of a normal expiration. For the passive assistance maneuvers, the physiotherapist encouraged patients to accept passively the insufflation by the MI-E device (passive inspiratory assistance), set initially at three different pressure levels (+20, +30, and +40 cmH2O). This pattern of increasing pressure levels was used to facilitate patients’ acceptance of the target pressure level of +40 cmH2O, since most patients
were not familiar with the device. This last measure (+ 40cmH2O) was then recorded (passive IC assistance). Passive exsufflation was then applied, with a pressure of -40 cmH2O (passive ERV assistance). Finally, insufflation at +40 cmH2O followed by exsufflation at -40 cmH2O was delivered (passive VC assistance). For the active assistance maneuvers, the patients were encouraged to breathe in as deeply as possible then to exhale as completely as possible (i.e., to perform a slow VC maneuver) concomitantly with the delivery: of a positive inspiratory assistance of +40 cmH2O (active IC assistance); of a negative expiratory assistance of -40 cmH2O (active ERV assistance); and, finally of a delivery of positive inspiratory pressure followed by a negative expiratory pressure (active VC assistance). Thus, for the analysis, five different types of maneuver were performed with passive assistance (+20, +30, +40, -40 and 40cmH2O) and three with active assistance (+40, -40 and 40cmH2O); each maneuver was repeated three times, at intervals of at least 30 seconds. All patients used the same MI-E device (JH Emerson Co., Cambridge, MA, USA) 2.4 Measurements (Figure 1) During the protocol maneuver, the patients breathed through a circuit connected to a number 2 Fleisch pneumotachograph (Fleisch, Lausanne, Switzerland) for the measurements of flow, and a differential pressure transducer (MP 45100cmH2O; Validyne Engineering Corp., Northridge, CA, USA) for the measurements of airway pressure. Flow and airway pressure were sampled at 1000Hz and recorded using an analogic-numeric system (MP 150, Biopac System, Goleta, CA, USA) with it software. When the patients performed the maneuvers with the MI-E device, this circuit was then attached to this device, which provided inspiratory and expiratory assistances. 2.5. Recorded Variables The following parameters were recorded: VC, total lung capacity (TLC), residual volume (RV), expiratory reserve volume (ERV), functional residual capacity (FRC), inspiratory capacity (IC), unassisted peak cough flow (PCF), maximum expiratory pressure
(MEP), maximum inspiratory pressure (MIP), and sniff measurements (Heritier et al., 1994; Prigent et al., 2004). Preliminary tests were conducted during a single session. Flow-volume curves, as well as PCF, MIP, MEP, and sniff were obtained during repeated maneuvers, the best value was recorded. During passive assistance, we recorded the lowest volumes obtained to optimally characterize the passivity of the patient, following a previously described principle (Azarian et al., 1993). During active maneuvers, the highest volumes were recorded for analysis, as the objective was to achieve the highest possible VC. Thus, the measurements were performed at baseline, under passive and active assistances. Minimal (for passive assistance) or Maximal (for active assistance) value were recorded. 2.6. Data analysis Data are described as mean±standard deviation, except in the figures, which show median [interquartile range]. Spirometry values are reported as percentage of the predicted normal value. The serial measures or the protocol (baseline, passive and active assistances) were compared using ANOVA (repeated measures) with a post-hoc Fisher’s test. The analysis between the same assistance in different NMDs was done by One-way ANOVA with a posthoc Fisher’s test. Linear regression analysis was performed to evaluate correlations between two values. P values <0.05 were considered significant. Statistical tests were run using the StatView 5 package (SAS Institute, Grenoble, France).
3. RESULTS Among the 54 included patients, 7 were excluded for failure to complete the protocol. The remaining 47 patients (30 males) completed the measurements (Figure 1). The patients had 20 different NMDs, but 25 (51%) patients had one of the three following diagnoses: Duchenne muscular dystrophy (DMD), n=9; myotonic dystrophy (MD), n=11; and spinal muscular atrophy (SMA), n=5. The remaining 22 patients had 17 diagnoses, and they were regrouped into an “other” category. Thus, we categorized the patients in four groups: Other pathologies (Other), DMD, MD and SMA. One DMD patient was a female heterozygous for a DMD mutation and is identified in all figures.
The anthropometric and respiratory characteristics, of the 4 different groups as well as IC, ERV and VC at baseline and with active and passive assistance are presented in Table 1 and 2. Overall, mean age was 41±14 years, mean VC was 37±18% of predicted, mean PCF 3.6±15 L/min, mean SNIP 30±16 cmH2O, mean MIP was 35±18 cmH2O, and mean MEP was 36±27 cmH2O. Only 6 patients were already familiar with the use of MI-E. Assisted VC values were significantly different across the four NMD categories (P=0.005) and the evolution of VC from baseline to passive and active assistances is presented in Figure 2A. No interaction was observed between the NMD categories and the response to VC assistance. Linear regression analysis demonstrated correlations linking baseline VC to VC with passive assistance (R2=0.49; P<0.0001) and to VC with active assistance (Figure 2B); VC with passive and active assistance were also correlated (R2=0.65; P<0.0001). Overall, our patients increased VC by 30% with active insufflation-exsufflation assistance, regardless of the type of NMD. Thus, VC became normal (>80% of predicted) in 11 (23%) patients, and a detailed analysis showed that these patients were MD and late-onset Pompe disease patients (from the “other” category) with onset of symptoms during adulthood. Among these 11 patients, improvement resulted from normalized IC values (>80% of predicted) with insufflation in 7 patients, normalized ERV values (>80% of predicted) with exsufflation in 3 patients, and normalization of both ERV and IC values in one patient. When the independent contribution of insufflation and exsufflation were assessed by measuring IC and ERV, respectively, we found that each alone failed to significantly increase VC. Assisted IC (figure 3A) varied significantly across the four NMD categories (P=0.0004) but no interaction was observed between NMD categories and the response to IC assistance. Active assistance yielded the largest IC improvement. Linear regression analysis showed a correlation linking baseline IC to IC with passive assistance (R2=0.57; P<0.0001) and with active assistance (Figure 3B); IC with passive assistance was also correlated to IC with active assistance (R2=0.75; P<0.0001). A subgroup analysis showed that 10 of the 11 MD patients and all 3 late-onset Pompe disease patients obtained normal IC with active inspiratory assistance, whereas DMD and other NMDs patients had more modest increases in IC values
that fell short of normal. The Figure 4A reports ERV values at baseline and with passive and active assistances. No interaction was detected between the NMD categories and the effects of expiratory assistance. By linear regression analysis, baseline ERV correlated with ERV during passive assistance (R2=0.22; P<0.0001) and during active assistance (Figure 4B); ERV values with passive and with active assistance were also correlated (R2=0.42; P<0.0001). Table 3 shows the analysis done to assess correlations linking baseline spirometry values to MIP and MEP.
4. DISCUSSION
Our study demonstrated that VC increased significantly with insufflation and exsufflation delivered with or without active patient participation. Overall, VC improved by 30% with active assistance, which was able to normalize VC (>80% of predicted) with active participation, in 11 (23%) patients. Compared to the other patients, these 11 patients presented a less severe respiratory involvement (i.e. presented less reduction in baseline VC), and also had later onset of symptoms, developed during adulthood (MD and late-onset Pompe Disease). The efficacy of assistance regardless of the severity of the respiratory involvement is supported by the absence of interactions between the effects of assistance on VC, IC, or ERV and the underlying NMD. We noticed that VC gains resulted mainly from insufflation, whereas exsufflation provided only a modest increase. At baseline, both VC and IC presented a weak but significant correlation with inspiratory muscle strength, as reported previously (Trebbia et al., 2005), suggesting that VC gains achieved in our study were chiefly ascribable to inspiratory assistance. This is supported by our finding that active insufflation generated normal IC values in 18 (38%) patients. In these patients, treatments able to restore inspiratory muscle strength would be expected to normalize respiratory volume. In a comparable manner, we found that inspiratory active assistance was not able to normalized IC values for the patients with earlier onset respiratory muscle weakness (as in
DMD). This finding suggests, similarly to earlier studies, that inspiratory muscle assistance of +40 cmH2O failed to normalize IC in some patients (McKim et al., 2012; Sancho et al., 2004), who were therefore unable to achieve the plateau of the volume-pressure curve (Azarian et al., 1993; Mellies and Goebel, 2014). Patients with NMD symptoms onset in childhood had low baseline IC values, ranging from 10% to 25% of predicted (mean, 29%±12% vs. 62%±11% in patients with adult-onset), with a modest improvement to 40% of predicted during active inspiratory assistance. Abnormalities in lung and chest-wall development are likely to exist in patients with early muscle weakness (Fauroux and Khirani, 2014). Nevertheless, in these patients, improving lung volumes might increase life expectancy (Kohler et al., 2009). In contrast, patients with later onset respiratory muscle weakness (as in MD or Pompe disease) were able to achieve normal spirometry values with assistance. Exsufflation significantly improved ERV, although this effect was smaller than that of insufflation on IC. We found no significant relationship between MEP and ERV. One possible explanation is upper airway collapse during negative pressure delivery as reported previously in patients with amyotrophic lateral sclerosis (Sancho et al., 2004). Therefore, this simple evaluation, i.e. measuring the spirometric variables produced via positive inspiratory and/or negative expiratory assistances, may help to identify the potential reversibility of lung restriction for some NMDs. Thus, in a situation in which a treatment is able to restore muscle function (Braun, 2013; Vulin et al., 2012), we could identify the patients who would benefit the most from this treatment. Indeed, VC and maximal pressures are usually used as endpoint to evaluate the impact of treatment on the respiratory function of NMD patients (Buyse et al., 2015; van der Ploeg et al., 2010). However, respiratory dysfunction may not only be limited to respiratory muscle weakness but may be multifactorial; patients unable to normalize their spirometric variables with assistance prior to treatment would be unlikely to do so even with an efficient treatment of respiratory muscle strength. Therefore, this type of evaluation would help to improve the appreciation of treatment efficiency. The passive assistance allowed to assess spirometric variables reversibility independently from patient’s participation and showed that volumes could improve when
compared to baseline with this non-volitional maneuver. However, greatest improvement was obtained with active assistance (implying the active participation of the patients) indicating for the patients who normalized their volumes the additional pressure level that their respiratory muscles would require to generate in order to normalize respiratory function. Study limitations One limitation of our study is that a single trial of insufflation and exsufflation was performed, which may be insufficient to achieve optimal lung volumes. Moreover, we assessed only the immediate effects of respiratory muscle assistance and not possible long term effects. Kang and Bach (2010) observed improvements in lung volumes in patients trained in achieving maximal lung insufflations three times a day. This may be ascribable to improvements in lung and chest-wall compliance. Thus, Stehling et al. (2015) reported an increase in conventional VC with no improvement in maximal pressure in patients who used insufflation/exsufflation for 10 minutes twice daily. They also suggest that respiratory system compliance could improve over time with treatments capable of improving inspiratory muscle strength. This leads to another limitation of our study as we did not perform chest wall and lung compliance measurements, which would have provided more detailed information on the elastic properties of the respiratory system. However, these measurements require invasive measurement using oesophagal pressure measurement; they also require respiratory muscle relaxation which is usually obtained either in trained subjects (American Thoracic Society/European Respiratory, 2002) or with the use of mechanical ventilation in order to induce respiratory muscles relaxation (Azarian et al., 1993); this type of evaluation is difficult to achieve in a routine context, especially in the absence of prior experience with mechanical ventilation. Moreover, while it would be of great interest to analyze the elastic properties of the respiratory system and to assess the respective participation of respiratory muscle weakness, chest wall and lung compliance potential decrease in the restrictive ventilator pattern of NMD patients, compliance measurements would not by themselves give us information on the potential reversibility of the volume reduction exhibited by patients. Another limitation is that a positive pressure level of 40 cmH2O may fail to achieve a
normal TLC in some patients. However, while we limited pressure support level to avoid barotrauma and other adverse effects, its level is consistent with guidelines about cough assistance (Benditt, 2006; Bott et al., 2009).
5. CONCLUSION In NMDs patients with respiratory-muscle weakness, MI-E assistance increases the inspiratory component of VC and, to a lesser extent, its expiratory component. This effect is seen in all NMDs types but is greatest in patients with late-onset NMD, who may achieve normal VC values with MI-E assistance. Active participation of the patients increases lung volume gains. Our findings indicate that inspiratory assistance of +40 cmH2O may restore normal IC values in some patients. In other patients, however, the lung volume restriction may persist, probably due to decreased respiratory system compliance in patients with early onset disease. The evaluation performed in our study may help to predict the likeliness of respiratory function normalization and help in the evaluation of the efficiency of potential treatments aiming to restore muscle strength.
Summary conflict of interest statements Dante Brasil Santos has no conflicts of interest regarding this article. Aurélien Boré has no conflicts of interest regarding this article. Lorena Del Amo Castrillo has no conflicts of interest regarding this article. Matthieu Lacombe has no conflicts of interest regarding this article. Line Falaize has no conflicts of interest regarding this article. David Orlikowski has no conflicts of interest regarding this article. Frédéric Lofaso has no conflicts of interest regarding this article. Hélène Prigent has no conflicts of interest regarding this article.
Funding information: Dante Brasil Santos received a PhD grant from the University of Brazilia and from the Brazilian Ministry of Research. The funding source had no involvement in the conduction of the study and the writing of the manuscript. ADEP assistance (A French homecare ventilation provider) promoted the study. ADEP assistance had no involvement in the conduction of the study and the writing of the manuscript.
Figure 1- Consort flow chart of the study. Figure 2 –Panel A: Evolution of vital capacity in all NMD patients during the different types of assistance. VC differed significantly across the baseline, passive assistance, and active assistance conditions (P<0.0001). The post-hoc Fisher test confirmed that assistance improved VC values. This effect was greatest for active assistance. Thus, baseline VC differed significantly from VC with passive or active assistance (* P<0.0001 for both), and VC with passive assistance differed significantly from VC with active assistance (** P=0.01) Panel B: Regression line between Active VC Assistance (±40 cmH2O) and Baseline VC. Full line: regression line; dotted line: identity line. Abbreviations: VC: vital capacity; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Figure 3 - Panel A: Inspiratory Capacity in all NMD patients during the different types of assistance showed a significant from baseline to passive and active assistance (P<0.0001). Post-hoc Fisher test confirmed that assistance improved IC values. Active assistance yielded the largest improvement. Thus, baseline IC was significantly lower than IC with passive or active assistance (* P<0.0001 for both). IC was significantly better with active than with passive assistance (** P=0.02) Panel B: Regression line between IC Active Inspiratory Assistance at 40 cmH2O (% of predicted) and Baseline IC (% of predicted). Full line: regression line; dotted line: identity line. Abbreviations: IC: inspiratory capacity; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Figure 4 - Panel A: Mean expiratory reserve volume in all NMD patients during the different types of assistance for expiration. . Panel B: Regression line between Active ERV Assistance (% of predicted) and Baseline ERV (% of predicted). Full line: regression line; dotted line: identity line. ANOVA p= 0.0002
* p=0.008 Abbreviations: ERV: expiratory reserve volume; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
References. Allen, J., 2010. Pulmonary complications of neuromuscular disease: a respiratory mechanics perspective. Paediatr Respir Rev 11, 18-23. American Thoracic Society/European Respiratory, S., 2002. ATS/ERS Statement on respiratory muscle testing. American journal of respiratory and critical care medicine 166, 518624. Azarian, R., Lofaso, F., Zerah, F., Lorino, H., Atlan, G., Isabey, D., Harf, A., 1993. Assessment of the respiratory compliance in awake subjects using pressure support. The European respiratory journal 6, 552-558. Benditt, J.O., 2006. The neuromuscular respiratory system: physiology, pathophysiology, and a respiratory care approach to patients. Respir Care 51, 829-837; discussion 837-829. Bott, J., Blumenthal, S., Buxton, M., Ellum, S., Falconer, C., Garrod, R., Harvey, A., Hughes, T., Lincoln, M., Mikelsons, C., Potter, C., Pryor, J., Rimington, L., Sinfield, F., Thompson, C., Vaughn, P., White, J., British Thoracic Society Physiotherapy Guideline Development, G., 2009. Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax 64 Suppl 1, i1-51. Braun, S., 2013. Gene-based therapies of neuromuscular disorders: an update and the pivotal role of patient organizations in their discovery and implementation. J Gene Med 15, 397-413. Buyse, G.M., Voit, T., Schara, U., Straathof, C.S., D'Angelo, M.G., Bernert, G., Cuisset, J.M., Finkel, R.S., Goemans, N., McDonald, C.M., Rummey, C., Meier, T., Group, D.S., 2015. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet 385, 1748-1757. Estenne, M., Gevenois, P.A., Kinnear, W., Soudon, P., Heilporn, A., De Troyer, A., 1993. Lung volume restriction in patients with chronic respiratory muscle weakness: the role of microatelectasis. Thorax 48, 698-701. Fauroux, B., Guillemot, N., Aubertin, G., Nathan, N., Labit, A., Clement, A., Lofaso, F., 2008. Physiologic benefits of mechanical insufflation-exsufflation in children with neuromuscular diseases. Chest 133, 161-168. Fauroux, B., Khirani, S., 2014. Neuromuscular disease and respiratory physiology in children: putting lung function into perspective. Respirology 19, 782-791. Heritier, F., Rahm, F., Pasche, P., Fitting, J.W., 1994. Sniff nasal inspiratory pressure. A noninvasive assessment of inspiratory muscle strength. American journal of respiratory and critical care medicine 150, 1678-1683. Kohler, M., Clarenbach, C.F., Bahler, C., Brack, T., Russi, E.W., Bloch, K.E., 2009. Disability and survival in Duchenne muscular dystrophy. Journal of neurology, neurosurgery, and psychiatry 80, 320-325.
McKim, D.A., Katz, S.L., Barrowman, N., Ni, A., LeBlanc, C., 2012. Lung volume recruitment slows pulmonary function decline in Duchenne muscular dystrophy. Arch Phys Med Rehabil 93, 1117-1122. Mellies, U., Goebel, C., 2014. Optimum insufflation capacity and peak cough flow in neuromuscular disorders. Ann Am Thorac Soc 11, 1560-1568. Misuri, G., Lanini, B., Gigliotti, F., Iandelli, I., Pizzi, A., Bertolini, M.G., Scano, G., 2000. Mechanism of CO(2) retention in patients with neuromuscular disease. Chest 117, 447-453. Perrin, C., Unterborn, J.N., Ambrosio, C.D., Hill, N.S., 2004. Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 29, 5-27. Phillips, M.F., Quinlivan, R.C., Edwards, R.H., Calverley, P.M., 2001. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. American journal of respiratory and critical care medicine 164, 2191-2194. Prigent, H., Lejaille, M., Falaize, L., Louis, A., Ruquet, M., Fauroux, B., Raphael, J.C., Lofaso, F., 2004. Assessing inspiratory muscle strength by sniff nasal inspiratory pressure. Neurocrit Care 1, 475-478. Prigent, H., Orlikowski, D., Laforet, P., Letilly, N., Falaize, L., Pellegrini, N., Annane, D., Raphael, J.C., Lofaso, F., 2012. Supine volume drop and diaphragmatic function in adults with Pompe disease. The European respiratory journal 39, 1545-1546. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1993. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 16, 5-40. Romei, M., D'Angelo, M.G., LoMauro, A., Gandossini, S., Bonato, S., Brighina, E., Marchi, E., Comi, G.P., Turconi, A.C., Pedotti, A., Bresolin, N., Aliverti, A., 2012. Low abdominal contribution to breathing as daytime predictor of nocturnal desaturation in adolescents and young adults with Duchenne Muscular Dystrophy. Respir Med 106, 276-283. Sancho, J., Servera, E., Diaz, J., Marin, J., 2004. Efficacy of mechanical insufflationexsufflation in medically stable patients with amyotrophic lateral sclerosis. Chest 125, 14001405. Trebbia, G., Lacombe, M., Fermanian, C., Falaize, L., Lejaille, M., Louis, A., Devaux, C., Raphael, J.C., Lofaso, F., 2005. Cough determinants in patients with neuromuscular disease. Respir Physiol Neurobiol 146, 291-300. van der Ploeg, A.T., Clemens, P.R., Corzo, D., Escolar, D.M., Florence, J., Groeneveld, G.J., Herson, S., Kishnani, P.S., Laforet, P., Lake, S.L., Lange, D.J., Leshner, R.T., Mayhew, J.E., Morgan, C., Nozaki, K., Park, D.J., Pestronk, A., Rosenbloom, B., Skrinar, A., van Capelle, C.I., van der Beek, N.A., Wasserstein, M., Zivkovic, S.A., 2010. A randomized study of alglucosidase alfa in late-onset Pompe's disease. The New England journal of medicine 362, 1396-1406.
Vulin, A., Barthelemy, I., Goyenvalle, A., Thibaud, J.L., Beley, C., Griffith, G., Benchaouir, R., le Hir, M., Unterfinger, Y., Lorain, S., Dreyfus, P., Voit, T., Carlier, P., Blot, S., Garcia, L., 2012. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping. Mol Ther 20, 2120-2133. Welch, M.A., Jr., Shapiro, B.J., Mercurio, P., Wagner, W., Hirayama, G., 1980. Methods of intermittent positive pressure breathing. Chest 78, 463-467.
Figr-1
Figr 2
Figr 3
Figr 4
Table 1: Anthropometric and respiratory characteristics of patients at baseline Other (n = 22)
SMA (n=5)
DMD (n=9)
MD (n=11)
Sex ratio (M/F)
14/8
2/3
8/1
6/5
Age
47±13 α β
33±10 γ
28±13 γ δ
45±11 β
PCF (L/min)
3.9±1.6
3.2±1.3
2.5±1.3
4.1±1.4
SNIP (cmH2O)
29±15 δ
42±19 β
17±7 α δ
41±14 β γ
MIP (cmH2O)
37±20
45±22
24±7
38±13
MEP (cmH2O)
47±34
27±14
21±11
32±14
α P<0.05 vs. SMA; β P<0.05 vs. DMD; δ P<0.05 vs. MD; γ P<0.05 vs Other.
Abbreviations: SMA, spinal muscular atrophy; DMD, Duchenne muscular dystrophy; MD, myotonic dystrophy; M, male; F, female; PCF, peak cough flow; SNIP, sniff nasal pressure; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure.
Table 2 : Evolution of lung volumes upon passive and active assistance
Other (n = 22)
SMA (n=5)
DMD (n=9)
MD (n=11)
3917 β α
3719
2013
4712 β α
Passive Assistance
5519 β α
5920
3812
6315 β α
Active Assistance
6721 β α‡
6320 ‡
4813 ‡
7012 β α ‡
Baseline
4020 β α δ
4718
2110
5712 β α
Passive Assistance
5919 β δ
6723
4413
7514 β α
Active Assistance
6721 β α δ ‡
7019 ‡
4912 ‡
8812 β α *‡
3823 β
2125
2026
2926
β
4539
2520
4138
5347 *
4324 *
3624 *
Baseline VC (% of predicted)
IC (% of predicted)
Baseline ERV (% of predicted)
Passive Assistance
4831
Active Assistance
5327 β *
α P<0.05 vs. SMA; β P<0.05 vs. DMD; δ P<0.05 vs. MD; γ P<0.05 vs Other; *P<0.05 vs. Baseline; ‡ P<0.05 vs. Passive Assistance.
Abbreviations: SMA, spinal muscular atrophy; DMD, Duchenne muscular dystrophy; MD, myotonic dystrophy; VC, vital capacity; IC, inspiratory capacity; ERV, expiratory reserve volume
Table 3 - Correlations linking baseline spirometry values with maximal inspiratory pressure and maximal expiratory pressure R2
P value
Baseline VC vs MIP
0.08
0.04
Baseline VC vs MEP
0.09
0.03
Baseline IC vs MIP
0.16
0.004
Baseline ERV vs MEP
0.02
0.25
Baseline IC vs MEP
0.125
0.01
Baseline ERV vs MIP
0.001
0.82
Abbreviations: VC, vital capacity; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure; IC, inspiratory capacity; ERV, expiratory reserve volume.
S1569-9048(17)30145-3 http://dx.doi.org/doi:10.1016/j.resp.2017.05.001 RESPNB 2807
To appear in:
Respiratory Physiology & Neurobiology
Received date: Revised date: Accepted date:
28-12-2015 27-4-2017 4-5-2017
Please cite this article as: Santos, Dante B, Bor´e, Aur´elien, Castrillo, Lorena Del Amo, Lacombe, Matthieu, Falaize, Line, Orlikowski, David, Lofaso, Fr´ed´eric, Prigent, H´el`ene, Assisted Vital Capacity to Assess Recruitment Level in Neuromuscular Diseases.Respiratory Physiology and Neurobiology http://dx.doi.org/10.1016/j.resp.2017.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Assisted Vital Capacity to Assess Recruitment Level in Neuromuscular Diseases Dante B Santos PT, PhD;a,b Aurélien Boré, PT;c Lorena Del Amo Castrillo, PT;c Matthieu Lacombe, PT;c Line Falaize;d David Orlikowski MD, PhD;c,d Frédéric Lofaso, MD, PhD;a,e Hélène Prigent MD, PhDa,e a. INSERM U 1179 - Université de Versailles Saint Quentin en Yvelines, UFR des sciences de la Santé Bâtiment Simone Veil 2 avenue de la source de la Bièvre, 78 180 Montigny-leBretonneux, France b. Centro de Fisioterapia e Reabilitação – Hospital Universitário de Brasília, Universidade de Brasília, Brasília-Distrito Federal, Brasilia, Brazil c. Service de Réanimation Médicale, APHP - Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France d. CIC 1429 – INSERM - APHP, Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France e. Physiologie - Explorations Fonctionnelles, APHP, Hôpital Raymond Poincaré, 104 bvd Raymond Poincaré, Garches, France Postal Address Mr Dante Brasil Santos : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Mr Aurélien Boré : [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Ms Lorena Del Amo Castrillo: [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Mr Matthieu Lacombe : [email protected] Service Réanimation Médicale, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Ms Line Falaize : [email protected] CIC 1429 – INSERM - APHP, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Pr David Orlikowski : [email protected] CIC 1429 – INSERM - APHP, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France
Pr Frédéric Lofaso : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Dr Hélène Prigent : [email protected] Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Corresponding Author Dr Hélène Prigent Service Physiologie - Explorations Fonctionnelles, CHU R. Poincaré, 104 Bvd Raymond Poincaré, 92380, Garches, France Phone number : 33-1-7107940 Fax number : 33-1-47107943 E-mail: [email protected] HighlightsNeuromuscular disease may induce respiratory muscle weakness and reduced volumes Improvement of spirometry volumes with mechanical In-Exsufflation was assessed A ±40cmH2O mechanical assistance may normalize reduced respiratory volumes Improvement is greatest in patients with late-onset neuromuscular disease
Abstract Respiratory muscle weakness and chest wall abnormalities in neuromuscular diseases (NMD) may lead to decreased pulmonary volumes. We assessed the reversibility of vital capacity (VC) reduction with mechanical In-Exsufflation (MI-E). We evaluated the effects of positive inspiratory and negative expiratory pressures on spirometric variables under passive (without patients’ participation) and active (with active participation) application in 47 NMD patients. VC, inspiratory capacity (IC), expiratory reserve volume (ERV) were measured during maneuvers without and with MI-E assistance, delivering inspiratory assistance (+40cmH2O), expiratory assistance (-40cmH2O) and both (+/40cmH2O). Passive and active assistance improved significantly VC and IC compared to baseline (P<0.0001 for both). ERV improved only with active assistance which normalized VC in 10, IC in 18 and ERV in 6 patients, mainly in patients with late-onset NMD. MI-E assistance produced greater increases in IC than in ERV, resulting in a VC increase enhanced by patients’ active participation. This type of evaluation may help to evaluate the potential reversibility of restrictive ventilatory pattern in NMDs .
Abbreviations: F: female; M: male; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Keywords: Neuromuscular disorders. Lung volume measurements. Mechanical insufflationexsufflation. Noninvasive respiratory aids; Vital capacity; Volume recruitment.
1.
INTRODUCTION
Overtime, increased morbidity and mortality in neuromuscular diseases (NMDs) is mainly due to impaired respiratory function (Phillips et al., 2001). These diseases are heterogeneous in their evolution, especially in the mechanism and severity of respiratory involvement. It is usually characterized by a restrictive ventilatory pattern caused initially by factors such as respiratory muscle weakness (Phillips et al., 2001) and subsequently also by alterations in the mechanical properties of the respiratory system (Allen, 2010; Perrin et al., 2004). Respiratory muscle weakness leads also to a chronic decrease in chest-wall motion that reflects connective-tissue stiffening and is exacerbated by structural chest-wall abnormalities (Misuri et al., 2000; Perrin et al., 2004). Moreover, atelectasis and chronic decrease in tidal volume (VT) may decrease lung compliance (Estenne et al., 1993; Romei et al., 2012). These mechanical alterations increase the load on weakened respiratory muscles, thereby creating a vicious circle of respiratory dysfunction (Perrin et al., 2004). Permanent chest-wall and lungtissue changes decrease the ability of respiratory-muscle strength improvements to restore a normal vital capacity (VC). Biomechanical and physical considerations suggest that the forces required to overcome the flow-resistive, inertial, and elastic properties of the respiratory system can be produced by the respiratory muscles (e.g., during conventional spirometry maneuvers), by passive in-exsufflation (Welch et al., 1980), or by a combination of both (e.g., during conventional spirometry maneuvers assisted by in-exsufflation) (Fauroux et al., 2008; Sancho et al., 2004). To counterbalance the deleterious effects observed in NMDs, lung recruitment maneuvers have been used to preserve the elasticity of respiratory system (Welch et al., 1980). These recruitment maneuvers can be obtained, for example, by the use of a Mechanical InExsufflation (MI-E) device, which promotes an inspiratory assistance by the delivery of positive pressure, and an expiratory assistance by the creation of negative pressure. Information on the elastic behavior of the respiratory system of NMDs would be useful and the use of MIE, while the patients let themselves be passively insufflated and exsufflated by the device, may allow to indirectly appreciate the elastic properties of the respiratory system, by assessing the
improvement in spirometric volumes. The active participation of the patients during the use of MI-E could in turn help to determine the support necessary to normalize lung volumes and capacities. Highlighting this potential reversibility of lung volumes reduction could identify whether an increase of lung volumes could be expected in case of respiratory muscle strength improvement or if underlying modifications of the elastic properties of the respiratory system would prevent any amelioration in that situation. Thus, by delivering positive pressure insufflation, it is possible to enhance the inspiratory capacity (IC), and likewise providing negative pressure exsufflation is liable to enhance the expiratory reserve volume (Sancho et al., 2004), improving then vital capacity by gains in IC and/or also in ERV. We aimed to assess the ability of NMDs patients to normalize their lung volumes when provided additional noninvasive support by MI-E assistance. In this situation, MI-E acts as a substitute for the effects of respiratory muscles (Azarian et al., 1993). Therefore we evaluated the potential reversibility of spirometric variables and capacities reduction by the delivery of a positive inspiratory pressure and negative expiratory pressure provided by MI-E, during both passive condition (while the patients let themselves be passively insufflated and exsufflated by the device) and active condition (while the patients actively participate to the insufflation an exsufflation maneuvers during slow VC maneuvers), in NMDs patients.
2. METHODS The study was performed between May 2013 and October 2014 at the home ventilation unit of the medical intensive care unit of the Raymond Poincaré Teaching Hospital (Garches, France), after being approved by the ethics committee (CPP IDF 11 – SaintGermain-en-Laye, France, Number2013-A00218-37) and registered on ClinicalTrials.gov. (Number 02022072). 2.1 Participants Adult patients with NMDs and a respiratory involvement defined as VC values lower than 80% of predicted (Quanjer et al., 1993) were solicited during their routine follow-up visits at the unit. Patients with tracheostomy and/or pulmonary disease contraindicating
hyperinsufflation and the use of a MI-E device were excluded. Written informed consent was collected from each patient. As the study aimed to test the ability of pressure support to reverse completely respiratory volume decrease, there was not enough data in the literature to perform a power calculation. In order to explore as many NMDs as possible for this pilot study, we wanted to analyze 50 patients and, therefore, decided to include 55 patients in order to take into account the risk of withdrawal during protocol in this fragile population. 2.2. Initial evaluation At this time, spirometry variables, lung volumes, Maximal static inspiratory (MIP) and expiratory (MEP) pressures were measured using a Vmax 229 SensorMedics System (Yorba Linda, CA, USA) according to standard guidelines (Quanjer et al., 1993) using a flanged mouthpiece and a noseclip. MIP and MEP were measured at FRC and TLC, respectively. Peak cough flow (PCF) was measured using a facemask of appropriate size (Laerdal Medical, Limonest, France) instead of a mouthpiece; it was placed around the mouth to allow mouth opening and reduce cheek compliance. Great care was taken to avoid leaks during the maneuvers. 2.3. Protocol maneuvers (Figure 1) The patients were initially asked to breathe normally while seated comfortably and quietly for 2 minutes, during which respiratory rate and tidal volume were recorded. After these measures, three slow unassisted VC maneuvers were performed (baseline maneuvers). If values differed by more than 5% from the best value, further maneuvers were performed (Quanjer et al., 1993). The protocol of assistance by MI-E device was divided in passive and active assistances. MI-E assistance was always started at the end of a normal expiration. For the passive assistance maneuvers, the physiotherapist encouraged patients to accept passively the insufflation by the MI-E device (passive inspiratory assistance), set initially at three different pressure levels (+20, +30, and +40 cmH2O). This pattern of increasing pressure levels was used to facilitate patients’ acceptance of the target pressure level of +40 cmH2O, since most patients
were not familiar with the device. This last measure (+ 40cmH2O) was then recorded (passive IC assistance). Passive exsufflation was then applied, with a pressure of -40 cmH2O (passive ERV assistance). Finally, insufflation at +40 cmH2O followed by exsufflation at -40 cmH2O was delivered (passive VC assistance). For the active assistance maneuvers, the patients were encouraged to breathe in as deeply as possible then to exhale as completely as possible (i.e., to perform a slow VC maneuver) concomitantly with the delivery: of a positive inspiratory assistance of +40 cmH2O (active IC assistance); of a negative expiratory assistance of -40 cmH2O (active ERV assistance); and, finally of a delivery of positive inspiratory pressure followed by a negative expiratory pressure (active VC assistance). Thus, for the analysis, five different types of maneuver were performed with passive assistance (+20, +30, +40, -40 and 40cmH2O) and three with active assistance (+40, -40 and 40cmH2O); each maneuver was repeated three times, at intervals of at least 30 seconds. All patients used the same MI-E device (JH Emerson Co., Cambridge, MA, USA) 2.4 Measurements (Figure 1) During the protocol maneuver, the patients breathed through a circuit connected to a number 2 Fleisch pneumotachograph (Fleisch, Lausanne, Switzerland) for the measurements of flow, and a differential pressure transducer (MP 45100cmH2O; Validyne Engineering Corp., Northridge, CA, USA) for the measurements of airway pressure. Flow and airway pressure were sampled at 1000Hz and recorded using an analogic-numeric system (MP 150, Biopac System, Goleta, CA, USA) with it software. When the patients performed the maneuvers with the MI-E device, this circuit was then attached to this device, which provided inspiratory and expiratory assistances. 2.5. Recorded Variables The following parameters were recorded: VC, total lung capacity (TLC), residual volume (RV), expiratory reserve volume (ERV), functional residual capacity (FRC), inspiratory capacity (IC), unassisted peak cough flow (PCF), maximum expiratory pressure
(MEP), maximum inspiratory pressure (MIP), and sniff measurements (Heritier et al., 1994; Prigent et al., 2004). Preliminary tests were conducted during a single session. Flow-volume curves, as well as PCF, MIP, MEP, and sniff were obtained during repeated maneuvers, the best value was recorded. During passive assistance, we recorded the lowest volumes obtained to optimally characterize the passivity of the patient, following a previously described principle (Azarian et al., 1993). During active maneuvers, the highest volumes were recorded for analysis, as the objective was to achieve the highest possible VC. Thus, the measurements were performed at baseline, under passive and active assistances. Minimal (for passive assistance) or Maximal (for active assistance) value were recorded. 2.6. Data analysis Data are described as mean±standard deviation, except in the figures, which show median [interquartile range]. Spirometry values are reported as percentage of the predicted normal value. The serial measures or the protocol (baseline, passive and active assistances) were compared using ANOVA (repeated measures) with a post-hoc Fisher’s test. The analysis between the same assistance in different NMDs was done by One-way ANOVA with a posthoc Fisher’s test. Linear regression analysis was performed to evaluate correlations between two values. P values <0.05 were considered significant. Statistical tests were run using the StatView 5 package (SAS Institute, Grenoble, France).
3. RESULTS Among the 54 included patients, 7 were excluded for failure to complete the protocol. The remaining 47 patients (30 males) completed the measurements (Figure 1). The patients had 20 different NMDs, but 25 (51%) patients had one of the three following diagnoses: Duchenne muscular dystrophy (DMD), n=9; myotonic dystrophy (MD), n=11; and spinal muscular atrophy (SMA), n=5. The remaining 22 patients had 17 diagnoses, and they were regrouped into an “other” category. Thus, we categorized the patients in four groups: Other pathologies (Other), DMD, MD and SMA. One DMD patient was a female heterozygous for a DMD mutation and is identified in all figures.
The anthropometric and respiratory characteristics, of the 4 different groups as well as IC, ERV and VC at baseline and with active and passive assistance are presented in Table 1 and 2. Overall, mean age was 41±14 years, mean VC was 37±18% of predicted, mean PCF 3.6±15 L/min, mean SNIP 30±16 cmH2O, mean MIP was 35±18 cmH2O, and mean MEP was 36±27 cmH2O. Only 6 patients were already familiar with the use of MI-E. Assisted VC values were significantly different across the four NMD categories (P=0.005) and the evolution of VC from baseline to passive and active assistances is presented in Figure 2A. No interaction was observed between the NMD categories and the response to VC assistance. Linear regression analysis demonstrated correlations linking baseline VC to VC with passive assistance (R2=0.49; P<0.0001) and to VC with active assistance (Figure 2B); VC with passive and active assistance were also correlated (R2=0.65; P<0.0001). Overall, our patients increased VC by 30% with active insufflation-exsufflation assistance, regardless of the type of NMD. Thus, VC became normal (>80% of predicted) in 11 (23%) patients, and a detailed analysis showed that these patients were MD and late-onset Pompe disease patients (from the “other” category) with onset of symptoms during adulthood. Among these 11 patients, improvement resulted from normalized IC values (>80% of predicted) with insufflation in 7 patients, normalized ERV values (>80% of predicted) with exsufflation in 3 patients, and normalization of both ERV and IC values in one patient. When the independent contribution of insufflation and exsufflation were assessed by measuring IC and ERV, respectively, we found that each alone failed to significantly increase VC. Assisted IC (figure 3A) varied significantly across the four NMD categories (P=0.0004) but no interaction was observed between NMD categories and the response to IC assistance. Active assistance yielded the largest IC improvement. Linear regression analysis showed a correlation linking baseline IC to IC with passive assistance (R2=0.57; P<0.0001) and with active assistance (Figure 3B); IC with passive assistance was also correlated to IC with active assistance (R2=0.75; P<0.0001). A subgroup analysis showed that 10 of the 11 MD patients and all 3 late-onset Pompe disease patients obtained normal IC with active inspiratory assistance, whereas DMD and other NMDs patients had more modest increases in IC values
that fell short of normal. The Figure 4A reports ERV values at baseline and with passive and active assistances. No interaction was detected between the NMD categories and the effects of expiratory assistance. By linear regression analysis, baseline ERV correlated with ERV during passive assistance (R2=0.22; P<0.0001) and during active assistance (Figure 4B); ERV values with passive and with active assistance were also correlated (R2=0.42; P<0.0001). Table 3 shows the analysis done to assess correlations linking baseline spirometry values to MIP and MEP.
4. DISCUSSION
Our study demonstrated that VC increased significantly with insufflation and exsufflation delivered with or without active patient participation. Overall, VC improved by 30% with active assistance, which was able to normalize VC (>80% of predicted) with active participation, in 11 (23%) patients. Compared to the other patients, these 11 patients presented a less severe respiratory involvement (i.e. presented less reduction in baseline VC), and also had later onset of symptoms, developed during adulthood (MD and late-onset Pompe Disease). The efficacy of assistance regardless of the severity of the respiratory involvement is supported by the absence of interactions between the effects of assistance on VC, IC, or ERV and the underlying NMD. We noticed that VC gains resulted mainly from insufflation, whereas exsufflation provided only a modest increase. At baseline, both VC and IC presented a weak but significant correlation with inspiratory muscle strength, as reported previously (Trebbia et al., 2005), suggesting that VC gains achieved in our study were chiefly ascribable to inspiratory assistance. This is supported by our finding that active insufflation generated normal IC values in 18 (38%) patients. In these patients, treatments able to restore inspiratory muscle strength would be expected to normalize respiratory volume. In a comparable manner, we found that inspiratory active assistance was not able to normalized IC values for the patients with earlier onset respiratory muscle weakness (as in
DMD). This finding suggests, similarly to earlier studies, that inspiratory muscle assistance of +40 cmH2O failed to normalize IC in some patients (McKim et al., 2012; Sancho et al., 2004), who were therefore unable to achieve the plateau of the volume-pressure curve (Azarian et al., 1993; Mellies and Goebel, 2014). Patients with NMD symptoms onset in childhood had low baseline IC values, ranging from 10% to 25% of predicted (mean, 29%±12% vs. 62%±11% in patients with adult-onset), with a modest improvement to 40% of predicted during active inspiratory assistance. Abnormalities in lung and chest-wall development are likely to exist in patients with early muscle weakness (Fauroux and Khirani, 2014). Nevertheless, in these patients, improving lung volumes might increase life expectancy (Kohler et al., 2009). In contrast, patients with later onset respiratory muscle weakness (as in MD or Pompe disease) were able to achieve normal spirometry values with assistance. Exsufflation significantly improved ERV, although this effect was smaller than that of insufflation on IC. We found no significant relationship between MEP and ERV. One possible explanation is upper airway collapse during negative pressure delivery as reported previously in patients with amyotrophic lateral sclerosis (Sancho et al., 2004). Therefore, this simple evaluation, i.e. measuring the spirometric variables produced via positive inspiratory and/or negative expiratory assistances, may help to identify the potential reversibility of lung restriction for some NMDs. Thus, in a situation in which a treatment is able to restore muscle function (Braun, 2013; Vulin et al., 2012), we could identify the patients who would benefit the most from this treatment. Indeed, VC and maximal pressures are usually used as endpoint to evaluate the impact of treatment on the respiratory function of NMD patients (Buyse et al., 2015; van der Ploeg et al., 2010). However, respiratory dysfunction may not only be limited to respiratory muscle weakness but may be multifactorial; patients unable to normalize their spirometric variables with assistance prior to treatment would be unlikely to do so even with an efficient treatment of respiratory muscle strength. Therefore, this type of evaluation would help to improve the appreciation of treatment efficiency. The passive assistance allowed to assess spirometric variables reversibility independently from patient’s participation and showed that volumes could improve when
compared to baseline with this non-volitional maneuver. However, greatest improvement was obtained with active assistance (implying the active participation of the patients) indicating for the patients who normalized their volumes the additional pressure level that their respiratory muscles would require to generate in order to normalize respiratory function. Study limitations One limitation of our study is that a single trial of insufflation and exsufflation was performed, which may be insufficient to achieve optimal lung volumes. Moreover, we assessed only the immediate effects of respiratory muscle assistance and not possible long term effects. Kang and Bach (2010) observed improvements in lung volumes in patients trained in achieving maximal lung insufflations three times a day. This may be ascribable to improvements in lung and chest-wall compliance. Thus, Stehling et al. (2015) reported an increase in conventional VC with no improvement in maximal pressure in patients who used insufflation/exsufflation for 10 minutes twice daily. They also suggest that respiratory system compliance could improve over time with treatments capable of improving inspiratory muscle strength. This leads to another limitation of our study as we did not perform chest wall and lung compliance measurements, which would have provided more detailed information on the elastic properties of the respiratory system. However, these measurements require invasive measurement using oesophagal pressure measurement; they also require respiratory muscle relaxation which is usually obtained either in trained subjects (American Thoracic Society/European Respiratory, 2002) or with the use of mechanical ventilation in order to induce respiratory muscles relaxation (Azarian et al., 1993); this type of evaluation is difficult to achieve in a routine context, especially in the absence of prior experience with mechanical ventilation. Moreover, while it would be of great interest to analyze the elastic properties of the respiratory system and to assess the respective participation of respiratory muscle weakness, chest wall and lung compliance potential decrease in the restrictive ventilator pattern of NMD patients, compliance measurements would not by themselves give us information on the potential reversibility of the volume reduction exhibited by patients. Another limitation is that a positive pressure level of 40 cmH2O may fail to achieve a
normal TLC in some patients. However, while we limited pressure support level to avoid barotrauma and other adverse effects, its level is consistent with guidelines about cough assistance (Benditt, 2006; Bott et al., 2009).
5. CONCLUSION In NMDs patients with respiratory-muscle weakness, MI-E assistance increases the inspiratory component of VC and, to a lesser extent, its expiratory component. This effect is seen in all NMDs types but is greatest in patients with late-onset NMD, who may achieve normal VC values with MI-E assistance. Active participation of the patients increases lung volume gains. Our findings indicate that inspiratory assistance of +40 cmH2O may restore normal IC values in some patients. In other patients, however, the lung volume restriction may persist, probably due to decreased respiratory system compliance in patients with early onset disease. The evaluation performed in our study may help to predict the likeliness of respiratory function normalization and help in the evaluation of the efficiency of potential treatments aiming to restore muscle strength.
Summary conflict of interest statements Dante Brasil Santos has no conflicts of interest regarding this article. Aurélien Boré has no conflicts of interest regarding this article. Lorena Del Amo Castrillo has no conflicts of interest regarding this article. Matthieu Lacombe has no conflicts of interest regarding this article. Line Falaize has no conflicts of interest regarding this article. David Orlikowski has no conflicts of interest regarding this article. Frédéric Lofaso has no conflicts of interest regarding this article. Hélène Prigent has no conflicts of interest regarding this article.
Funding information: Dante Brasil Santos received a PhD grant from the University of Brazilia and from the Brazilian Ministry of Research. The funding source had no involvement in the conduction of the study and the writing of the manuscript. ADEP assistance (A French homecare ventilation provider) promoted the study. ADEP assistance had no involvement in the conduction of the study and the writing of the manuscript.
Figure 1- Consort flow chart of the study. Figure 2 –Panel A: Evolution of vital capacity in all NMD patients during the different types of assistance. VC differed significantly across the baseline, passive assistance, and active assistance conditions (P<0.0001). The post-hoc Fisher test confirmed that assistance improved VC values. This effect was greatest for active assistance. Thus, baseline VC differed significantly from VC with passive or active assistance (* P<0.0001 for both), and VC with passive assistance differed significantly from VC with active assistance (** P=0.01) Panel B: Regression line between Active VC Assistance (±40 cmH2O) and Baseline VC. Full line: regression line; dotted line: identity line. Abbreviations: VC: vital capacity; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Figure 3 - Panel A: Inspiratory Capacity in all NMD patients during the different types of assistance showed a significant from baseline to passive and active assistance (P<0.0001). Post-hoc Fisher test confirmed that assistance improved IC values. Active assistance yielded the largest improvement. Thus, baseline IC was significantly lower than IC with passive or active assistance (* P<0.0001 for both). IC was significantly better with active than with passive assistance (** P=0.02) Panel B: Regression line between IC Active Inspiratory Assistance at 40 cmH2O (% of predicted) and Baseline IC (% of predicted). Full line: regression line; dotted line: identity line. Abbreviations: IC: inspiratory capacity; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
Figure 4 - Panel A: Mean expiratory reserve volume in all NMD patients during the different types of assistance for expiration. . Panel B: Regression line between Active ERV Assistance (% of predicted) and Baseline ERV (% of predicted). Full line: regression line; dotted line: identity line. ANOVA p= 0.0002
* p=0.008 Abbreviations: ERV: expiratory reserve volume; DMD: Duchenne muscular dystrophy; MD: myotonic dystrophy; SMA: spinal muscular atrophy
References. Allen, J., 2010. Pulmonary complications of neuromuscular disease: a respiratory mechanics perspective. Paediatr Respir Rev 11, 18-23. American Thoracic Society/European Respiratory, S., 2002. ATS/ERS Statement on respiratory muscle testing. American journal of respiratory and critical care medicine 166, 518624. Azarian, R., Lofaso, F., Zerah, F., Lorino, H., Atlan, G., Isabey, D., Harf, A., 1993. Assessment of the respiratory compliance in awake subjects using pressure support. The European respiratory journal 6, 552-558. Benditt, J.O., 2006. The neuromuscular respiratory system: physiology, pathophysiology, and a respiratory care approach to patients. Respir Care 51, 829-837; discussion 837-829. Bott, J., Blumenthal, S., Buxton, M., Ellum, S., Falconer, C., Garrod, R., Harvey, A., Hughes, T., Lincoln, M., Mikelsons, C., Potter, C., Pryor, J., Rimington, L., Sinfield, F., Thompson, C., Vaughn, P., White, J., British Thoracic Society Physiotherapy Guideline Development, G., 2009. Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax 64 Suppl 1, i1-51. Braun, S., 2013. Gene-based therapies of neuromuscular disorders: an update and the pivotal role of patient organizations in their discovery and implementation. J Gene Med 15, 397-413. Buyse, G.M., Voit, T., Schara, U., Straathof, C.S., D'Angelo, M.G., Bernert, G., Cuisset, J.M., Finkel, R.S., Goemans, N., McDonald, C.M., Rummey, C., Meier, T., Group, D.S., 2015. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet 385, 1748-1757. Estenne, M., Gevenois, P.A., Kinnear, W., Soudon, P., Heilporn, A., De Troyer, A., 1993. Lung volume restriction in patients with chronic respiratory muscle weakness: the role of microatelectasis. Thorax 48, 698-701. Fauroux, B., Guillemot, N., Aubertin, G., Nathan, N., Labit, A., Clement, A., Lofaso, F., 2008. Physiologic benefits of mechanical insufflation-exsufflation in children with neuromuscular diseases. Chest 133, 161-168. Fauroux, B., Khirani, S., 2014. Neuromuscular disease and respiratory physiology in children: putting lung function into perspective. Respirology 19, 782-791. Heritier, F., Rahm, F., Pasche, P., Fitting, J.W., 1994. Sniff nasal inspiratory pressure. A noninvasive assessment of inspiratory muscle strength. American journal of respiratory and critical care medicine 150, 1678-1683. Kohler, M., Clarenbach, C.F., Bahler, C., Brack, T., Russi, E.W., Bloch, K.E., 2009. Disability and survival in Duchenne muscular dystrophy. Journal of neurology, neurosurgery, and psychiatry 80, 320-325.
McKim, D.A., Katz, S.L., Barrowman, N., Ni, A., LeBlanc, C., 2012. Lung volume recruitment slows pulmonary function decline in Duchenne muscular dystrophy. Arch Phys Med Rehabil 93, 1117-1122. Mellies, U., Goebel, C., 2014. Optimum insufflation capacity and peak cough flow in neuromuscular disorders. Ann Am Thorac Soc 11, 1560-1568. Misuri, G., Lanini, B., Gigliotti, F., Iandelli, I., Pizzi, A., Bertolini, M.G., Scano, G., 2000. Mechanism of CO(2) retention in patients with neuromuscular disease. Chest 117, 447-453. Perrin, C., Unterborn, J.N., Ambrosio, C.D., Hill, N.S., 2004. Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 29, 5-27. Phillips, M.F., Quinlivan, R.C., Edwards, R.H., Calverley, P.M., 2001. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. American journal of respiratory and critical care medicine 164, 2191-2194. Prigent, H., Lejaille, M., Falaize, L., Louis, A., Ruquet, M., Fauroux, B., Raphael, J.C., Lofaso, F., 2004. Assessing inspiratory muscle strength by sniff nasal inspiratory pressure. Neurocrit Care 1, 475-478. Prigent, H., Orlikowski, D., Laforet, P., Letilly, N., Falaize, L., Pellegrini, N., Annane, D., Raphael, J.C., Lofaso, F., 2012. Supine volume drop and diaphragmatic function in adults with Pompe disease. The European respiratory journal 39, 1545-1546. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1993. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 16, 5-40. Romei, M., D'Angelo, M.G., LoMauro, A., Gandossini, S., Bonato, S., Brighina, E., Marchi, E., Comi, G.P., Turconi, A.C., Pedotti, A., Bresolin, N., Aliverti, A., 2012. Low abdominal contribution to breathing as daytime predictor of nocturnal desaturation in adolescents and young adults with Duchenne Muscular Dystrophy. Respir Med 106, 276-283. Sancho, J., Servera, E., Diaz, J., Marin, J., 2004. Efficacy of mechanical insufflationexsufflation in medically stable patients with amyotrophic lateral sclerosis. Chest 125, 14001405. Trebbia, G., Lacombe, M., Fermanian, C., Falaize, L., Lejaille, M., Louis, A., Devaux, C., Raphael, J.C., Lofaso, F., 2005. Cough determinants in patients with neuromuscular disease. Respir Physiol Neurobiol 146, 291-300. van der Ploeg, A.T., Clemens, P.R., Corzo, D., Escolar, D.M., Florence, J., Groeneveld, G.J., Herson, S., Kishnani, P.S., Laforet, P., Lake, S.L., Lange, D.J., Leshner, R.T., Mayhew, J.E., Morgan, C., Nozaki, K., Park, D.J., Pestronk, A., Rosenbloom, B., Skrinar, A., van Capelle, C.I., van der Beek, N.A., Wasserstein, M., Zivkovic, S.A., 2010. A randomized study of alglucosidase alfa in late-onset Pompe's disease. The New England journal of medicine 362, 1396-1406.
Vulin, A., Barthelemy, I., Goyenvalle, A., Thibaud, J.L., Beley, C., Griffith, G., Benchaouir, R., le Hir, M., Unterfinger, Y., Lorain, S., Dreyfus, P., Voit, T., Carlier, P., Blot, S., Garcia, L., 2012. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping. Mol Ther 20, 2120-2133. Welch, M.A., Jr., Shapiro, B.J., Mercurio, P., Wagner, W., Hirayama, G., 1980. Methods of intermittent positive pressure breathing. Chest 78, 463-467.
Figr-1
Figr 2
Figr 3
Figr 4
Table 1: Anthropometric and respiratory characteristics of patients at baseline Other (n = 22)
SMA (n=5)
DMD (n=9)
MD (n=11)
Sex ratio (M/F)
14/8
2/3
8/1
6/5
Age
47±13 α β
33±10 γ
28±13 γ δ
45±11 β
PCF (L/min)
3.9±1.6
3.2±1.3
2.5±1.3
4.1±1.4
SNIP (cmH2O)
29±15 δ
42±19 β
17±7 α δ
41±14 β γ
MIP (cmH2O)
37±20
45±22
24±7
38±13
MEP (cmH2O)
47±34
27±14
21±11
32±14
α P<0.05 vs. SMA; β P<0.05 vs. DMD; δ P<0.05 vs. MD; γ P<0.05 vs Other.
Abbreviations: SMA, spinal muscular atrophy; DMD, Duchenne muscular dystrophy; MD, myotonic dystrophy; M, male; F, female; PCF, peak cough flow; SNIP, sniff nasal pressure; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure.
Table 2 : Evolution of lung volumes upon passive and active assistance
Other (n = 22)
SMA (n=5)
DMD (n=9)
MD (n=11)
3917 β α
3719
2013
4712 β α
Passive Assistance
5519 β α
5920
3812
6315 β α
Active Assistance
6721 β α‡
6320 ‡
4813 ‡
7012 β α ‡
Baseline
4020 β α δ
4718
2110
5712 β α
Passive Assistance
5919 β δ
6723
4413
7514 β α
Active Assistance
6721 β α δ ‡
7019 ‡
4912 ‡
8812 β α *‡
3823 β
2125
2026
2926
β
4539
2520
4138
5347 *
4324 *
3624 *
Baseline VC (% of predicted)
IC (% of predicted)
Baseline ERV (% of predicted)
Passive Assistance
4831
Active Assistance
5327 β *
α P<0.05 vs. SMA; β P<0.05 vs. DMD; δ P<0.05 vs. MD; γ P<0.05 vs Other; *P<0.05 vs. Baseline; ‡ P<0.05 vs. Passive Assistance.
Abbreviations: SMA, spinal muscular atrophy; DMD, Duchenne muscular dystrophy; MD, myotonic dystrophy; VC, vital capacity; IC, inspiratory capacity; ERV, expiratory reserve volume
Table 3 - Correlations linking baseline spirometry values with maximal inspiratory pressure and maximal expiratory pressure R2
P value
Baseline VC vs MIP
0.08
0.04
Baseline VC vs MEP
0.09
0.03
Baseline IC vs MIP
0.16
0.004
Baseline ERV vs MEP
0.02
0.25
Baseline IC vs MEP
0.125
0.01
Baseline ERV vs MIP
0.001
0.82
Abbreviations: VC, vital capacity; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure; IC, inspiratory capacity; ERV, expiratory reserve volume.