- Email: [email protected]
Prognostic value of nocturnal hypoventilation in neuromuscular patients
Accepted Manuscript Title: Prognostic value of nocturnal hypoventilation in neuromuscular patients. Author: David Orlikowski, Helene Prigent, Maria-Antonia Quera Salva, Nicholas Heming, Cendrine Chaffaut, Sylvie Chevret, Djillali Annane, Frederic Lofaso, Adam Ogna PII: DOI: Reference:
S0960-8966(16)31054-9 http://dx.doi.org/doi: 10.1016/j.nmd.2016.12.006 NMD 3305
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
20-10-2016 29-11-2016 11-12-2016
Please cite this article as: David Orlikowski, Helene Prigent, Maria-Antonia Quera Salva, Nicholas Heming, Cendrine Chaffaut, Sylvie Chevret, Djillali Annane, Frederic Lofaso, Adam Ogna, Prognostic value of nocturnal hypoventilation in neuromuscular patients., Neuromuscular Disorders (2016), http://dx.doi.org/doi: 10.1016/j.nmd.2016.12.006. 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.
TITLE: Prognostic value of nocturnal hypoventilation in neuromuscular patients.
Running head: Nocturnal hypoventilation in neuromuscular disease
AUTHOR LIST: David Orlikowskia,b, MD, PhD; Helene Prigentc, MD, PhD; Maria-Antonia Quera Salvad, MD, PhD; Nicholas Heminga, MD, PhD; Cendrine Chaffaut, PhDe; Sylvie Chevrete, MD, PhD; Djillali Annanea, MD, PhD; Frederic Lofasoc,d, MD, PhD; Adam Ognaa,b, MD a. CHU Raymond Poincaré, Service de Réanimation médicale et unité de ventilation à domicile, 92380 Garches, France b. CHU Raymond Poincaré, INSERM CIC 14.29, 92380 Garches, France c. CHU Raymond Poincaré, Service de Physiologie-Explorations Fonctionnelles, 92380 Garches, France d. CHU Raymond Poincaré, Unité du Sommeil, 92380 Garches, France e. CHU Saint Louis, Service de Biostatistique et Information Médicale, 75475 Paris, France
Corresponding author : Dr Adam Ogna Service de Réanimation médicale et unité de ventilation à domicile AP-HP, Centre Hospitalier Universitaire Raymond Poincaré 92380 Garches, France e-mail : [email protected] Phone : +41795568188
Word count (main text): 2’606 Abstract word count: 260
1 Page 1 of 17
Summary conflict of interest statement All the authors declare that they have no conflict of interest related to the present work to disclose. The Service de Physiologie-Explorations Fonctionnelles of Garches received research funds from ResMed France, not related to the present work. The CIC 14.29 of Garches received research funds from BREAS Medical for a project on end-tidal CO2.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
HIGHLIGHTS:
Nocturnal hypercapnia may be present in daytime normocapnic neuromuscular patients.
Nocturnal hypercapnia seems to predict mechanical ventilation in follow-up.
Several cut-offs have been proposed to define nocturnal hypoventilation.
Peak TcCO2 should be the preferred criterion for nocturnal hypoventilation.
ABSTRACT: In neuromuscular disease (NMD) patients, current guidelines recommend the initiation of home mechanical ventilation (HMV) in case of daytime hypercapnia or nocturnal desaturation as an indirect sign of hypoventilation. Transcutaneous capno-oximetry (TcCO2) enables the direct assessment of nocturnal hypercapnia; however the best cut-off value remains to be defined. We aimed to compare the prognostic value of several published definitions of nocturnal hypercapnia, in a cohort of NMD patients.
2 Page 2 of 17
All consecutive TcCO2 recordings performed between 2010 and 2014 in unventilated adult NMD patients in a tertiary reference center were retrospectively collected. Initiation of HMV and mortality were collected as outcomes of interest. 124 patients with normal daytime blood gazes were analysed (median age 39 [IQR 31-55] years; vital capacity 61% [43-82] of predicted). The prevalence of nocturnal hypercapnia ranged from 3% to 44%, depending on the definition. Over a median follow-up duration of 2.5 years [IQR 1.6-4.1], HMV was initiated for 51 patients, while 4 patients died. Nocturnal peak TcCO2 ≥49 mmHg was the best predictor of HMV initiation in the follow-up, being associated with a hazard ratio of 2.6 [95%CI 1.4-4.6] in a multivariate analysis adjusting for lung function parameters. Nocturnal TcCO2 identifies NMD patients at risk for subsequent need for HMV in the following few years, who were not identified by daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, daytime hypercapnia, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity. Keywords: home mechanical ventilation; neuromuscular disease; restrictive respiratory failure; nocturnal hypoventilation; transcutaneous capno-oximetry
ClinicalTrials.gov identifier: NCT02356666.
3 Page 3 of 17
ABBREVIATIONS LIST:
CO2: carbon dioxide DMD: Duchenne or Becker muscular dystrophy HMV: home mechanical ventilation MD1: Myotonic dystrophy type 1 (Steinert’s Disease) NMD: Neuromuscular diseases PaCO2: partial arterial pressure of CO2 SMA: spinal muscular atrophy SpO2: oxygen saturation TcCO2: transcutaneous measure of CO2 VC: respiratory vital capacity
4 Page 4 of 17
1. INTRODUCTION: Respiratory muscles are involved in several neuromuscular diseases (NMD), resulting in restrictive respiratory failure and alveolar hypoventilation, in addition to impairment of peripheral motor capacity[1-5]. Respiratory failure through chronic hypoventilation is a leading cause of morbidity and mortality in NMD which can be effectively controlled by home mechanical ventilation (HMV), thereby improving the clinical course of NMD patients[1, 5-11]. Criteria to initiate ventilation in NMD have been defined in a 1999 consensus conference, without essential modification since then, namely the presence of symptomatic daytime hypercapnia or nocturnal desaturation, the latter being considered an indirect sign of nocturnal hypoventilation[12]. Meanwhile, a non-invasive transcutaneous CO2 monitoring tool (TcCO2) has become widely available, which enables a direct assessment of nocturnal hypoventilation. Several thresholds have recently been proposed to define nocturnal hypoventilation using capnometry, mostly relying on expert opinions[1, 10, 13-15]. In a recent analysis of a large, unselected NMD population we observed marked differences in the prevalence of hypoventilation according to the definition used[16]. Specifically, nocturnal TcCO2 monitoring identified nocturnal hypoventilation in up to one third of patients with daytime normocapnia. The proposed definitions of nocturnal hypoventilation have not been compared in their ability to predict relevant clinical outcomes, and thus the best strategy to detect nocturnal hypoventilation in daytime normocapnic NMD remains to be defined. This has practical consequences for both clinicians and researchers working in this field, since the decision to initiate HMV relies upon the detection of hypoventilation. The aim of our study was to evaluate the prognostic value of TcCO2, when used in addition to daytime blood gazes and nocturnal hypoxemia to detect hypoventilation, and to
5 Page 5 of 17
compare several published definitions of nocturnal hypercapnia, in a cohort of neuromuscular disease patients.
2. MATERIALS AND METHODS: 2.1. Patients Data were retrospectively collected from the charts of NMD adults, followed at the Home Mechanical Ventilation Unit of the Raymond Poincare teaching Hospital, Garches, France, a tertiary reference center for neuromuscular diseases. According to the regional organisation of reference centres for rare diseases, amyotrophic lateral sclerosis patients are not followed at our reference centre. Non-ventilated neuromuscular patients are hospitalized at least annually for follow-up in our unit, and at each visit, sleep recording and daytime blood gases are performed to assess the indication to start mechanical ventilation. All consecutive capno-oximetries performed in unventilated patients between 2010 and 2014 were reviewed and the first recording of each patient was retained for analysis. Patients for whom a decision to start HMV based on the findings of the baseline capno-oximetry were excluded. Recordings performed with oxygen therapy were also excluded. The study was conducted in accordance with the declaration of Helsinki and was approved by the French national regulatory board (CNIL, N.1817118). ClinicalTrials.gov identifier: NCT02356666. 2.2. Capno-oximetry and Daytime blood gases Overnight continuous TcCO2 and oxygen saturation (SpO2) were monitored using a Digital Monitoring
System
(SenTec,
Therwil,
Switzerland)
equipped
with
a
combined
Severinghaus-type TcCO2 electrode and SpO2 sensor (V-Sign, SenTec, Therwil, Switzerland). As recommended by the manufacturer, the electrode was calibrated in the integrated docking station before and after each measurement to adjust for calibration drift, 6 Page 6 of 17
using a service gas mixture (8% CO2, 12% O2, and 80% N2). All studies were visually inspected by the same investigator (AO) in order to exclude any periods containing artefacts from the results. According to routine clinical practice in the unit, daytime blood gas values were obtained on the morning following capno-oximetry. Blood samples were drawn at rest and immediately carried in an ice bag to the central hospital laboratory for analysis. 2.3. Definition of nocturnal Hypoventilation Nocturnal hypoventilation was defined as: - TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes, in accordance with the proposition of the American Academy for Sleep Medicine (hereinafter referred to as “[AASM]” definition)[13, 14] - peak TcCO2 ≥49 mmHg, according to the cut-off used by Ward et al (“[Ward]” definition)[10, 15] - mean TcCO2 >50 mmHg, as suggested in a recent paper by Simonds (“[Simonds]” definition)[1] 2.4. Outcomes We considered initiation of mechanical ventilation (either planned according to the 1999 consensus conference criteria[12], namely in the presence of symptoms of hypoventilation associated with daytime arterial PaCO2 ≥45 mmHg or nocturnal desaturation ≤88% for 5 consecutive minutes, or emergent following acute ventilatory failure) and mortality as outcomes of interest for the present analysis. Four patients were started on HMV on the basis of symptomatic nocturnal hypercapnia without meeting the consensus criteria, and were not considered among the studied outcomes for the present analysis. 2.5. Statistical analysis Continuous variables were described by median ± interquartile range (IQR); dichotomous 7 Page 7 of 17
or categorical variables were described by number of subjects and percentage. Outcomes were analysed by computing cumulative incidence curves, and compared using Gray's test. A multivariable Cox model was then used to estimate the strength of association based on hazard ratio (HR), adjusting for the demographic, respiratory function and blood gazes factors that showed significant association with the outcome in univariate analyses. Statistical analysis was conducted using R statistical software (R Core Team, www.rproject.org).
3. RESULTS: 3.1. Study population A total of 128 capno-oximetries fulfilling the inclusion criteria were performed between 2010 and 2014. Data from 124 patients were analyzed for the present study, after exclusion of 4 patients because of missing follow-up data. Furthermore, 100 additional recordings performed over the same time period were not included because an indication to promptly initiate HMV was retained. Patients suffered from 48 different types of NMD, the most frequent being Myotonic dystrophy type 1 (MD1; N=48), Spinal muscular atrophy (N=13), Limb girdle muscular dystrophies (N=11), and Duchenne or Becker muscular dystrophy (N=9); no patient suffered from amyotrophic lateral sclerosis (ALS). Characteristics of the study population are detailed in Table 1. TcCO2 identified nocturnal hypoventilation in 3.2 to 44.4 % of the patients, according to the definition used (Figure 1). 3.2. Outcomes Over a follow-up period of up to 6.5 years (median 2.5 years [IQR 1.6 - 4.1]), 51 patients fulfilled the predetermined criteria for HMV initiation. The cumulative incidence of HMV was of 33.3% at 2 years and of 71.9% at 5 years (Figure 2). Twenty-four patients were 8 Page 8 of 17
ventilated because of daytime hypercapnia; 22 because of symptomatic nocturnal hypoxemia and 5 patients presented acute ventilatory failure requiring emergency treatment in the intensive care unit (ICU). Overall four deaths (3.2%) occurred, two of which followed emergent initiation of ventilation. One death was due to acute respiratory failure, whilst the fourth cause of death was undetermined. 3.3. Prognostic factors Among the various criteria for nocturnal hypoventilation, only [AASM] and [Ward] identified subgroups of patients with a significantly increased risk of subsequent ventilation (Figure 3), whilst [Simonds] was non-discriminatory. However, the [Ward] definition classified 55 patients as being at risk (Hazard Ratio (HR) 2.68, p<0.0001), compared to only 17 patients identified by the [AASM] definition (HR 2.67, p=0.002). During the first 2 years of follow-up, mechanical ventilation was initiated in 35 patients; the [Ward] definition identified 22 of these patients (sensitivity 62.9%, specificity 35.3%) as being at risk, whilst the [AASM] definition depicted only 9 patients (sensitivity 25.7%, specificity 80.0%). Relying on these differences, we selected the [Ward] definition to be used in the multivariable model, which included respiratory vital capacity, maximal inspiratory pressure (PI max), arterial PCO2, and serum bicarbonates as covariables. In the final model, nocturnal hypercapnia (HR 2.56 [95%CI: 1.43 - 4.59], p=0.002) and respiratory vital capacity (HR 1.22 [1.11 - 1.35] for each 10% decrease in VC, p=0.003) both independently identified patients with a significantly increased risk of subsequent mechanical ventilation. A similar prognostic value of the [Ward] definition of hypoventilation (HR 2.64, p=0.045) was found analysing the subgroup of patients with Myotonic dystrophy type 1 (Steinert’s Disease, N=48), as well as in the subgroup of patients affected by muscular dystrophies (N=23, HR 3.47, p=0.041), which represented the two largest disease subgroups of the study population. Neuromuscular disease type, age, gender and age at first disease’s manifestation were not predictive of subsequent need for mechanical ventilation. 9 Page 9 of 17
4. DISCUSSION: We report the first data comparing the prognostic value of several definitions of nocturnal hypoventilation in the presence of daytime normocapnia, in neuromuscular patients. Our data show that TcCO2 adds valuable prognostic information to the currently recommended monitoring by daytime blood gazes and nocturnal oximetry, allowing to identify at an earlier stage NMD patients who are developing respiratory failure. In a previous analysis of the NMD population followed at our reference center, we showed marked differences in the prevalence of hypoventilation according to different definitions proposed in the literature[16]. In particular, the use of the non-invasive nocturnal TcCO2 monitoring identified nocturnal hypoventilation in up to one third of patients with normocapnia on daytime blood gazes. However, because of its cross-sectional design, our previous study was unable to inform on the best definition to be used. Indeed, the best definition of nocturnal hypoventilation is still a matter of debate, since the various reported definitions rely solely on expert opinions. The current work addresses this issue, comparing the most commonly used definitions in their ability to predict a clinical relevant outcome: the need to initiate HMV. Detecting nocturnal hypoventilation in the absence of daytime hypercapnia has a pathophysiological rationale, since nocturnal hypoventilation precedes the development of overt respiratory failure in NMD patients[1, 14]. In fact, respiratory impairment progresses over time in several NMD forms, reflecting the progression of respiratory muscle involvement. As such, hypoventilation manifests first during the night-time, initially only during the rapid-eye movement (REM) sleep because of the sleep-induced atony of the accessory respiratory muscles. As muscular impairment progresses, periods of hypoventilation
extend
to
non-REM
sleep,
evolving
lastly
into
persistent
hypoventilation[14]. Furthermore, the development of chronic hypercapnia leads to a 10 Page 10 of 17
blunted hypercapnic ventilatory drive, resulting in a vicious cycle[1]. Monitoring of nocturnal hypoventilation may help identify patients that enter this progressive respiratory decline, before the development of overt hypercapnia. Correcting nocturnal hypoventilation in patients with diurnal hypercapnia may yield clinically more obvious benefits than in patients with daytime normocapnia. However one of the few randomized trials existing in NMD showed that patients with nocturnal hypoventilation, defined as a peak TcCO2 ≥49 mmHg, would benefit of HMV even in the absence of daytime hypercapnia[9, 10]. On the other hand, older studies suggested a reduced survival in NMD patients treated with preventive (early) HMV reposing on respiratory function parameters [17]. These results suffer from several limitations, including the absence of night-time respiratory assessment, leading to uncertainty regarding the presence or not of sleep-disordered breathing upon HMV initiation. The existing evidence is consistent in identifying nocturnal hypoventilation without daytime hypercapnia as a marker of increased respiratory risk. Our study adds to this body of evidence, suggesting that the cut-off value used in the aforementioned study by Ward et al[10] (peak TcCO2 ≥49 mmHg) should be preferred, in neuromuscular patients. Despite the recent wider availability of TcCO2 in the clinical practice, thanks to the recent technical improvements of capnometry devices, the quality of the probes and the membranes, and the user-friendliness of the technique, TcCO2 accuracy is strongly dependent of appropriate handling and knowledge of the equipment and procedure[18]. The main limitations of our study are linked to its retrospective design. First of all, the criteria for HMV initiation were not predefined by a study protocol, as would be the case in a prospective study, but were the usual clinical practice of an expert center. To mitigate the risk of integrating TcCO2 results into the decision to initiate HMV, we excluded from the current analysis 4 patients who did not fulfil the indications described in the 1999 consensus conference[12]. On the other hand, we obtained data from a large unselected 11 Page 11 of 17
adult NMD population, referred to our unit to assess the need for HMV, which is exactly the clinical context where the studied definitions should be applied. A further limitation of our study is the impossibility to infer the prognostic effect of initiating ventilation to correct nocturnal hypoventilation, a point previously addressed by Ward et al[10], using the exact definition of nocturnal hypoventilation that we identified as the most discriminating. Contrasting with the study by Ward et al, in which 9/10 patients of the control group required HMV after 2 years of follow-up, we observed a cumulative incidence of HMV of 42.1% after 2 years in the subgroup with a peak TcCO2 ≥49 mmHg. This difference may partly be explained by the age difference between the study populations, since the adult forms of neuromuscular diseases investigated in our study exhibit a slower evolution than the paediatric forms studied by Ward. Furthermore, the criteria for initiating HMV in the latter study were more liberal than those we chose, with only 6/10 children fulfilling the 1999 consensus criteria[12] at the time of HMV onset and 3/10 being ventilated because of symptomatic nocturnal hypercapnia. Low mortality rates in our cohort preclude any statistical analysis relating to this outcome. However fatalities occurred in 2 cases following urgent initiation of mechanical ventilation and in a third (unventilated) patient because of respiratory failure, suggesting that an earlier identification of these patients could have mitigated this outcome. Criteria for initiating nocturnal mechanical ventilation may need to differ in rapidly progressive and less rapidly progressive NMD, since the delay from nocturnal hypoventilation to overt daytime hypercapnia may vary. We could not demonstrate any such difference in the various subgroups of our population. It should however be underlined that our study population does not include rapidly progressing ALS patients, and that the population of NMD patients that are not yet ventilated at adult age may represent a particular population with a rather slowly progressing disease. Despite the major advances in the field of HMV, there is still an essential need for good quality prospective trials with outcome measures that have clinical meaning, in order to 12 Page 12 of 17
define the best management strategy for each single neuromuscular disease, including the best timing/criteria to initiate ventilation, the ventilation strategy, but also airway and secretion management, cardiologic treatment and much others.
5. CONCLUSION: The main finding of our study is the fact that nocturnal TcCO2 identifies NMD patients at risk for subsequent need for HMV in the following few years; this subpopulation consists of patients who were not identified by the results of daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, hypercapnia on awake blood gas measurement, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity.
6. AKNOWLEDGMENTS: 6.1. Author contributions AO, HP, MQS, DA, FL and DO: designed the experiment; AO, HP, MQS, NH, DA and DO: conducted the research; AO, CC, SC, FL and DO: analysed the data and performed the statistical analyses; AO, HP, NH and DO: wrote the manuscript; AO and DO: have primary responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to all of the data (including statistical reports and tables) in the study, revised the manuscript for important intellectual content and approved the final version of the manuscript.
6.2. Summary conflict of interest statement All the authors declare that they have no conflict of interest related to the present work to disclose. 13 Page 13 of 17
The Service de Physiologie-Explorations Fonctionnelles of Garches received research funds from ResMed France, not related to the present work. The CIC 14.29 of Garches received research funds from BREAS Medical for a project on end-tidal CO2.
6.3. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
14 Page 14 of 17
7. REFERENCES: [1] [2] [3]
[4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
[14] [15] [16] [17]
[18]
Simonds AK. Chronic hypoventilation and its management. European respiratory review : an official journal of the European Respiratory Society 2013;22:325-32. Polkey MI, Lyall RA, Moxham J, Leigh PN. Respiratory aspects of neurological disease. J Neurol Neurosurg Psychiatry 1999;66:5-15. Norwood F, de Visser M, Eymard B, Lochmuller H, Bushby K, Force EGT. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. European journal of neurology : the official journal of the European Federation of Neurological Societies 2007;14:1305-12. Rimmer KP, Golar SD, Lee MA, Whitelaw WA. Myotonia of the respiratory muscles in myotonic dystrophy. Am Rev Respir Dis 1993;148:1018-22. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 2002;12:926-9. Simonds AK, Muntoni F, Heather S, Fielding S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998;53:949-52. Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy type 1. Neurology 2007;69:1931-6. Magnus T, Beck M, Giess R, Puls I, Naumann M, Toyka KV. Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve 2002;25:709-14. Annane D, Orlikowski D, Chevret S. Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. The Cochrane database of systematic reviews 2014;12:CD001941. Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005;60:1019-24. Bach JR, Goncalves MR, Hon A, et al. Changing trends in the management of end-stage neuromuscular respiratory muscle failure: recommendations of an international consensus. Am J Phys Med Rehabil 2013;92:267-77. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation--a consensus conference report. Chest 1999;116:521-34. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597-619. Loutfi S. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care Med 2015;doi: 10.1164/rccm.201412-2224CI. Nardi J, Prigent H, Adala A, et al. Nocturnal oximetry and transcutaneous carbon dioxide in home-ventilated neuromuscular patients. Respir Care 2012;57:1425-30. Ogna A, Quera Salva MA, Prigent H, et al. Nocturnal hypoventilation in neuromuscular disease: prevalence according to different definitions issued from the literature. Sleep & breathing = Schlaf & Atmung 2015. Raphael JC, Chevret S, Chastang C, Bouvet F. Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet 1994;343:1600-4. Aarrestad S, Tollefsen E, Kleiven AL, Qvarfort M, Janssens JP, Skjonsberg OH. Validity of transcutaneous PCO2 in monitoring chronic hypoventilation treated with non-invasive ventilation. Respir Med 2016;112:112-8.
15 Page 15 of 17
9. FIGURES: Figure 1: prevalence of nocturnal hypoventilation, according to the different definitions [AASM]: TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes; [Ward]: peak TcCO2 ≥49 mmHg; [Simonds]: mean TcCO2 >50 mmHg
Figure 2: cumulative incidence of the study outcomes over the follow-up period
Figure 3: cumulative incidence of ventilation, according to [AASM] (left panel) and [Ward] definition (right panel). [AASM]: TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes; [Ward]: peak TcCO2 ≥49 mmHg
16 Page 16 of 17
8. TABLES: Table 1: characteristics of the study population and capno-oximetry Characteristic Women (n, %)
70 (56.4)
Age (y)
39 [31 ;55]
Age of first symptoms (y)
17 [10 ;41]
Respiratory parameters VC sitting (%pred)
61 [43 ;82]
VC supine (%pred)
54 [34 ;73]
PI max (cmH2O)
42 [28 ;62]
PE max (cmH2O)
33 [22 ;46]
Daytime blood gases pH
7.41 [7.39 ;7.42]
PaCO2 (mmHg)
39.9 [37.8 ;42.4]
PaO2 (mmHg)
78.0 [69.8 ;94.5]
Bicarbonates (mmol/l)
25.2 [23.6 ;26.2]
Total CO2 (mmol/l)
26.5 [24.9 ;27.4]
Nocturnal Capno-Oximetry Duration of the recording (min)
481 [468 ;551]
Oxygen Desaturation Index (no./h)
5 [2 ;12.2]
Mean Oxygen Saturation (%)
96 [94 ;97]
Mean nocturnal TcCO2 (mmHg)
42.8 [39.6 ;45.5]
Max nocturnal TcCO2 (mmHg)
48.4 [44.2 ;51.0]
VC: vital capacity; %pred: percentage of the predicted value; PI max: maximal inspiratory pressure; PE max: maximal expiratory pressure; PaCO2: partial arterial pressure of carbon dioxide (CO2); PaO2: partial arterial oxygen pressure; TcCO2: transcutaneous measure of CO2 Values are expressed as median [IQR] or number of patients (%).
17 Page 17 of 17
S0960-8966(16)31054-9 http://dx.doi.org/doi: 10.1016/j.nmd.2016.12.006 NMD 3305
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
20-10-2016 29-11-2016 11-12-2016
Please cite this article as: David Orlikowski, Helene Prigent, Maria-Antonia Quera Salva, Nicholas Heming, Cendrine Chaffaut, Sylvie Chevret, Djillali Annane, Frederic Lofaso, Adam Ogna, Prognostic value of nocturnal hypoventilation in neuromuscular patients., Neuromuscular Disorders (2016), http://dx.doi.org/doi: 10.1016/j.nmd.2016.12.006. 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.
TITLE: Prognostic value of nocturnal hypoventilation in neuromuscular patients.
Running head: Nocturnal hypoventilation in neuromuscular disease
AUTHOR LIST: David Orlikowskia,b, MD, PhD; Helene Prigentc, MD, PhD; Maria-Antonia Quera Salvad, MD, PhD; Nicholas Heminga, MD, PhD; Cendrine Chaffaut, PhDe; Sylvie Chevrete, MD, PhD; Djillali Annanea, MD, PhD; Frederic Lofasoc,d, MD, PhD; Adam Ognaa,b, MD a. CHU Raymond Poincaré, Service de Réanimation médicale et unité de ventilation à domicile, 92380 Garches, France b. CHU Raymond Poincaré, INSERM CIC 14.29, 92380 Garches, France c. CHU Raymond Poincaré, Service de Physiologie-Explorations Fonctionnelles, 92380 Garches, France d. CHU Raymond Poincaré, Unité du Sommeil, 92380 Garches, France e. CHU Saint Louis, Service de Biostatistique et Information Médicale, 75475 Paris, France
Corresponding author : Dr Adam Ogna Service de Réanimation médicale et unité de ventilation à domicile AP-HP, Centre Hospitalier Universitaire Raymond Poincaré 92380 Garches, France e-mail : [email protected] Phone : +41795568188
Word count (main text): 2’606 Abstract word count: 260
1 Page 1 of 17
Summary conflict of interest statement All the authors declare that they have no conflict of interest related to the present work to disclose. The Service de Physiologie-Explorations Fonctionnelles of Garches received research funds from ResMed France, not related to the present work. The CIC 14.29 of Garches received research funds from BREAS Medical for a project on end-tidal CO2.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
HIGHLIGHTS:
Nocturnal hypercapnia may be present in daytime normocapnic neuromuscular patients.
Nocturnal hypercapnia seems to predict mechanical ventilation in follow-up.
Several cut-offs have been proposed to define nocturnal hypoventilation.
Peak TcCO2 should be the preferred criterion for nocturnal hypoventilation.
ABSTRACT: In neuromuscular disease (NMD) patients, current guidelines recommend the initiation of home mechanical ventilation (HMV) in case of daytime hypercapnia or nocturnal desaturation as an indirect sign of hypoventilation. Transcutaneous capno-oximetry (TcCO2) enables the direct assessment of nocturnal hypercapnia; however the best cut-off value remains to be defined. We aimed to compare the prognostic value of several published definitions of nocturnal hypercapnia, in a cohort of NMD patients.
2 Page 2 of 17
All consecutive TcCO2 recordings performed between 2010 and 2014 in unventilated adult NMD patients in a tertiary reference center were retrospectively collected. Initiation of HMV and mortality were collected as outcomes of interest. 124 patients with normal daytime blood gazes were analysed (median age 39 [IQR 31-55] years; vital capacity 61% [43-82] of predicted). The prevalence of nocturnal hypercapnia ranged from 3% to 44%, depending on the definition. Over a median follow-up duration of 2.5 years [IQR 1.6-4.1], HMV was initiated for 51 patients, while 4 patients died. Nocturnal peak TcCO2 ≥49 mmHg was the best predictor of HMV initiation in the follow-up, being associated with a hazard ratio of 2.6 [95%CI 1.4-4.6] in a multivariate analysis adjusting for lung function parameters. Nocturnal TcCO2 identifies NMD patients at risk for subsequent need for HMV in the following few years, who were not identified by daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, daytime hypercapnia, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity. Keywords: home mechanical ventilation; neuromuscular disease; restrictive respiratory failure; nocturnal hypoventilation; transcutaneous capno-oximetry
ClinicalTrials.gov identifier: NCT02356666.
3 Page 3 of 17
ABBREVIATIONS LIST:
CO2: carbon dioxide DMD: Duchenne or Becker muscular dystrophy HMV: home mechanical ventilation MD1: Myotonic dystrophy type 1 (Steinert’s Disease) NMD: Neuromuscular diseases PaCO2: partial arterial pressure of CO2 SMA: spinal muscular atrophy SpO2: oxygen saturation TcCO2: transcutaneous measure of CO2 VC: respiratory vital capacity
4 Page 4 of 17
1. INTRODUCTION: Respiratory muscles are involved in several neuromuscular diseases (NMD), resulting in restrictive respiratory failure and alveolar hypoventilation, in addition to impairment of peripheral motor capacity[1-5]. Respiratory failure through chronic hypoventilation is a leading cause of morbidity and mortality in NMD which can be effectively controlled by home mechanical ventilation (HMV), thereby improving the clinical course of NMD patients[1, 5-11]. Criteria to initiate ventilation in NMD have been defined in a 1999 consensus conference, without essential modification since then, namely the presence of symptomatic daytime hypercapnia or nocturnal desaturation, the latter being considered an indirect sign of nocturnal hypoventilation[12]. Meanwhile, a non-invasive transcutaneous CO2 monitoring tool (TcCO2) has become widely available, which enables a direct assessment of nocturnal hypoventilation. Several thresholds have recently been proposed to define nocturnal hypoventilation using capnometry, mostly relying on expert opinions[1, 10, 13-15]. In a recent analysis of a large, unselected NMD population we observed marked differences in the prevalence of hypoventilation according to the definition used[16]. Specifically, nocturnal TcCO2 monitoring identified nocturnal hypoventilation in up to one third of patients with daytime normocapnia. The proposed definitions of nocturnal hypoventilation have not been compared in their ability to predict relevant clinical outcomes, and thus the best strategy to detect nocturnal hypoventilation in daytime normocapnic NMD remains to be defined. This has practical consequences for both clinicians and researchers working in this field, since the decision to initiate HMV relies upon the detection of hypoventilation. The aim of our study was to evaluate the prognostic value of TcCO2, when used in addition to daytime blood gazes and nocturnal hypoxemia to detect hypoventilation, and to
5 Page 5 of 17
compare several published definitions of nocturnal hypercapnia, in a cohort of neuromuscular disease patients.
2. MATERIALS AND METHODS: 2.1. Patients Data were retrospectively collected from the charts of NMD adults, followed at the Home Mechanical Ventilation Unit of the Raymond Poincare teaching Hospital, Garches, France, a tertiary reference center for neuromuscular diseases. According to the regional organisation of reference centres for rare diseases, amyotrophic lateral sclerosis patients are not followed at our reference centre. Non-ventilated neuromuscular patients are hospitalized at least annually for follow-up in our unit, and at each visit, sleep recording and daytime blood gases are performed to assess the indication to start mechanical ventilation. All consecutive capno-oximetries performed in unventilated patients between 2010 and 2014 were reviewed and the first recording of each patient was retained for analysis. Patients for whom a decision to start HMV based on the findings of the baseline capno-oximetry were excluded. Recordings performed with oxygen therapy were also excluded. The study was conducted in accordance with the declaration of Helsinki and was approved by the French national regulatory board (CNIL, N.1817118). ClinicalTrials.gov identifier: NCT02356666. 2.2. Capno-oximetry and Daytime blood gases Overnight continuous TcCO2 and oxygen saturation (SpO2) were monitored using a Digital Monitoring
System
(SenTec,
Therwil,
Switzerland)
equipped
with
a
combined
Severinghaus-type TcCO2 electrode and SpO2 sensor (V-Sign, SenTec, Therwil, Switzerland). As recommended by the manufacturer, the electrode was calibrated in the integrated docking station before and after each measurement to adjust for calibration drift, 6 Page 6 of 17
using a service gas mixture (8% CO2, 12% O2, and 80% N2). All studies were visually inspected by the same investigator (AO) in order to exclude any periods containing artefacts from the results. According to routine clinical practice in the unit, daytime blood gas values were obtained on the morning following capno-oximetry. Blood samples were drawn at rest and immediately carried in an ice bag to the central hospital laboratory for analysis. 2.3. Definition of nocturnal Hypoventilation Nocturnal hypoventilation was defined as: - TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes, in accordance with the proposition of the American Academy for Sleep Medicine (hereinafter referred to as “[AASM]” definition)[13, 14] - peak TcCO2 ≥49 mmHg, according to the cut-off used by Ward et al (“[Ward]” definition)[10, 15] - mean TcCO2 >50 mmHg, as suggested in a recent paper by Simonds (“[Simonds]” definition)[1] 2.4. Outcomes We considered initiation of mechanical ventilation (either planned according to the 1999 consensus conference criteria[12], namely in the presence of symptoms of hypoventilation associated with daytime arterial PaCO2 ≥45 mmHg or nocturnal desaturation ≤88% for 5 consecutive minutes, or emergent following acute ventilatory failure) and mortality as outcomes of interest for the present analysis. Four patients were started on HMV on the basis of symptomatic nocturnal hypercapnia without meeting the consensus criteria, and were not considered among the studied outcomes for the present analysis. 2.5. Statistical analysis Continuous variables were described by median ± interquartile range (IQR); dichotomous 7 Page 7 of 17
or categorical variables were described by number of subjects and percentage. Outcomes were analysed by computing cumulative incidence curves, and compared using Gray's test. A multivariable Cox model was then used to estimate the strength of association based on hazard ratio (HR), adjusting for the demographic, respiratory function and blood gazes factors that showed significant association with the outcome in univariate analyses. Statistical analysis was conducted using R statistical software (R Core Team, www.rproject.org).
3. RESULTS: 3.1. Study population A total of 128 capno-oximetries fulfilling the inclusion criteria were performed between 2010 and 2014. Data from 124 patients were analyzed for the present study, after exclusion of 4 patients because of missing follow-up data. Furthermore, 100 additional recordings performed over the same time period were not included because an indication to promptly initiate HMV was retained. Patients suffered from 48 different types of NMD, the most frequent being Myotonic dystrophy type 1 (MD1; N=48), Spinal muscular atrophy (N=13), Limb girdle muscular dystrophies (N=11), and Duchenne or Becker muscular dystrophy (N=9); no patient suffered from amyotrophic lateral sclerosis (ALS). Characteristics of the study population are detailed in Table 1. TcCO2 identified nocturnal hypoventilation in 3.2 to 44.4 % of the patients, according to the definition used (Figure 1). 3.2. Outcomes Over a follow-up period of up to 6.5 years (median 2.5 years [IQR 1.6 - 4.1]), 51 patients fulfilled the predetermined criteria for HMV initiation. The cumulative incidence of HMV was of 33.3% at 2 years and of 71.9% at 5 years (Figure 2). Twenty-four patients were 8 Page 8 of 17
ventilated because of daytime hypercapnia; 22 because of symptomatic nocturnal hypoxemia and 5 patients presented acute ventilatory failure requiring emergency treatment in the intensive care unit (ICU). Overall four deaths (3.2%) occurred, two of which followed emergent initiation of ventilation. One death was due to acute respiratory failure, whilst the fourth cause of death was undetermined. 3.3. Prognostic factors Among the various criteria for nocturnal hypoventilation, only [AASM] and [Ward] identified subgroups of patients with a significantly increased risk of subsequent ventilation (Figure 3), whilst [Simonds] was non-discriminatory. However, the [Ward] definition classified 55 patients as being at risk (Hazard Ratio (HR) 2.68, p<0.0001), compared to only 17 patients identified by the [AASM] definition (HR 2.67, p=0.002). During the first 2 years of follow-up, mechanical ventilation was initiated in 35 patients; the [Ward] definition identified 22 of these patients (sensitivity 62.9%, specificity 35.3%) as being at risk, whilst the [AASM] definition depicted only 9 patients (sensitivity 25.7%, specificity 80.0%). Relying on these differences, we selected the [Ward] definition to be used in the multivariable model, which included respiratory vital capacity, maximal inspiratory pressure (PI max), arterial PCO2, and serum bicarbonates as covariables. In the final model, nocturnal hypercapnia (HR 2.56 [95%CI: 1.43 - 4.59], p=0.002) and respiratory vital capacity (HR 1.22 [1.11 - 1.35] for each 10% decrease in VC, p=0.003) both independently identified patients with a significantly increased risk of subsequent mechanical ventilation. A similar prognostic value of the [Ward] definition of hypoventilation (HR 2.64, p=0.045) was found analysing the subgroup of patients with Myotonic dystrophy type 1 (Steinert’s Disease, N=48), as well as in the subgroup of patients affected by muscular dystrophies (N=23, HR 3.47, p=0.041), which represented the two largest disease subgroups of the study population. Neuromuscular disease type, age, gender and age at first disease’s manifestation were not predictive of subsequent need for mechanical ventilation. 9 Page 9 of 17
4. DISCUSSION: We report the first data comparing the prognostic value of several definitions of nocturnal hypoventilation in the presence of daytime normocapnia, in neuromuscular patients. Our data show that TcCO2 adds valuable prognostic information to the currently recommended monitoring by daytime blood gazes and nocturnal oximetry, allowing to identify at an earlier stage NMD patients who are developing respiratory failure. In a previous analysis of the NMD population followed at our reference center, we showed marked differences in the prevalence of hypoventilation according to different definitions proposed in the literature[16]. In particular, the use of the non-invasive nocturnal TcCO2 monitoring identified nocturnal hypoventilation in up to one third of patients with normocapnia on daytime blood gazes. However, because of its cross-sectional design, our previous study was unable to inform on the best definition to be used. Indeed, the best definition of nocturnal hypoventilation is still a matter of debate, since the various reported definitions rely solely on expert opinions. The current work addresses this issue, comparing the most commonly used definitions in their ability to predict a clinical relevant outcome: the need to initiate HMV. Detecting nocturnal hypoventilation in the absence of daytime hypercapnia has a pathophysiological rationale, since nocturnal hypoventilation precedes the development of overt respiratory failure in NMD patients[1, 14]. In fact, respiratory impairment progresses over time in several NMD forms, reflecting the progression of respiratory muscle involvement. As such, hypoventilation manifests first during the night-time, initially only during the rapid-eye movement (REM) sleep because of the sleep-induced atony of the accessory respiratory muscles. As muscular impairment progresses, periods of hypoventilation
extend
to
non-REM
sleep,
evolving
lastly
into
persistent
hypoventilation[14]. Furthermore, the development of chronic hypercapnia leads to a 10 Page 10 of 17
blunted hypercapnic ventilatory drive, resulting in a vicious cycle[1]. Monitoring of nocturnal hypoventilation may help identify patients that enter this progressive respiratory decline, before the development of overt hypercapnia. Correcting nocturnal hypoventilation in patients with diurnal hypercapnia may yield clinically more obvious benefits than in patients with daytime normocapnia. However one of the few randomized trials existing in NMD showed that patients with nocturnal hypoventilation, defined as a peak TcCO2 ≥49 mmHg, would benefit of HMV even in the absence of daytime hypercapnia[9, 10]. On the other hand, older studies suggested a reduced survival in NMD patients treated with preventive (early) HMV reposing on respiratory function parameters [17]. These results suffer from several limitations, including the absence of night-time respiratory assessment, leading to uncertainty regarding the presence or not of sleep-disordered breathing upon HMV initiation. The existing evidence is consistent in identifying nocturnal hypoventilation without daytime hypercapnia as a marker of increased respiratory risk. Our study adds to this body of evidence, suggesting that the cut-off value used in the aforementioned study by Ward et al[10] (peak TcCO2 ≥49 mmHg) should be preferred, in neuromuscular patients. Despite the recent wider availability of TcCO2 in the clinical practice, thanks to the recent technical improvements of capnometry devices, the quality of the probes and the membranes, and the user-friendliness of the technique, TcCO2 accuracy is strongly dependent of appropriate handling and knowledge of the equipment and procedure[18]. The main limitations of our study are linked to its retrospective design. First of all, the criteria for HMV initiation were not predefined by a study protocol, as would be the case in a prospective study, but were the usual clinical practice of an expert center. To mitigate the risk of integrating TcCO2 results into the decision to initiate HMV, we excluded from the current analysis 4 patients who did not fulfil the indications described in the 1999 consensus conference[12]. On the other hand, we obtained data from a large unselected 11 Page 11 of 17
adult NMD population, referred to our unit to assess the need for HMV, which is exactly the clinical context where the studied definitions should be applied. A further limitation of our study is the impossibility to infer the prognostic effect of initiating ventilation to correct nocturnal hypoventilation, a point previously addressed by Ward et al[10], using the exact definition of nocturnal hypoventilation that we identified as the most discriminating. Contrasting with the study by Ward et al, in which 9/10 patients of the control group required HMV after 2 years of follow-up, we observed a cumulative incidence of HMV of 42.1% after 2 years in the subgroup with a peak TcCO2 ≥49 mmHg. This difference may partly be explained by the age difference between the study populations, since the adult forms of neuromuscular diseases investigated in our study exhibit a slower evolution than the paediatric forms studied by Ward. Furthermore, the criteria for initiating HMV in the latter study were more liberal than those we chose, with only 6/10 children fulfilling the 1999 consensus criteria[12] at the time of HMV onset and 3/10 being ventilated because of symptomatic nocturnal hypercapnia. Low mortality rates in our cohort preclude any statistical analysis relating to this outcome. However fatalities occurred in 2 cases following urgent initiation of mechanical ventilation and in a third (unventilated) patient because of respiratory failure, suggesting that an earlier identification of these patients could have mitigated this outcome. Criteria for initiating nocturnal mechanical ventilation may need to differ in rapidly progressive and less rapidly progressive NMD, since the delay from nocturnal hypoventilation to overt daytime hypercapnia may vary. We could not demonstrate any such difference in the various subgroups of our population. It should however be underlined that our study population does not include rapidly progressing ALS patients, and that the population of NMD patients that are not yet ventilated at adult age may represent a particular population with a rather slowly progressing disease. Despite the major advances in the field of HMV, there is still an essential need for good quality prospective trials with outcome measures that have clinical meaning, in order to 12 Page 12 of 17
define the best management strategy for each single neuromuscular disease, including the best timing/criteria to initiate ventilation, the ventilation strategy, but also airway and secretion management, cardiologic treatment and much others.
5. CONCLUSION: The main finding of our study is the fact that nocturnal TcCO2 identifies NMD patients at risk for subsequent need for HMV in the following few years; this subpopulation consists of patients who were not identified by the results of daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, hypercapnia on awake blood gas measurement, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity.
6. AKNOWLEDGMENTS: 6.1. Author contributions AO, HP, MQS, DA, FL and DO: designed the experiment; AO, HP, MQS, NH, DA and DO: conducted the research; AO, CC, SC, FL and DO: analysed the data and performed the statistical analyses; AO, HP, NH and DO: wrote the manuscript; AO and DO: have primary responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to all of the data (including statistical reports and tables) in the study, revised the manuscript for important intellectual content and approved the final version of the manuscript.
6.2. Summary conflict of interest statement All the authors declare that they have no conflict of interest related to the present work to disclose. 13 Page 13 of 17
The Service de Physiologie-Explorations Fonctionnelles of Garches received research funds from ResMed France, not related to the present work. The CIC 14.29 of Garches received research funds from BREAS Medical for a project on end-tidal CO2.
6.3. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
14 Page 14 of 17
7. REFERENCES: [1] [2] [3]
[4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
[14] [15] [16] [17]
[18]
Simonds AK. Chronic hypoventilation and its management. European respiratory review : an official journal of the European Respiratory Society 2013;22:325-32. Polkey MI, Lyall RA, Moxham J, Leigh PN. Respiratory aspects of neurological disease. J Neurol Neurosurg Psychiatry 1999;66:5-15. Norwood F, de Visser M, Eymard B, Lochmuller H, Bushby K, Force EGT. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. European journal of neurology : the official journal of the European Federation of Neurological Societies 2007;14:1305-12. Rimmer KP, Golar SD, Lee MA, Whitelaw WA. Myotonia of the respiratory muscles in myotonic dystrophy. Am Rev Respir Dis 1993;148:1018-22. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 2002;12:926-9. Simonds AK, Muntoni F, Heather S, Fielding S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998;53:949-52. Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy type 1. Neurology 2007;69:1931-6. Magnus T, Beck M, Giess R, Puls I, Naumann M, Toyka KV. Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve 2002;25:709-14. Annane D, Orlikowski D, Chevret S. Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. The Cochrane database of systematic reviews 2014;12:CD001941. Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005;60:1019-24. Bach JR, Goncalves MR, Hon A, et al. Changing trends in the management of end-stage neuromuscular respiratory muscle failure: recommendations of an international consensus. Am J Phys Med Rehabil 2013;92:267-77. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation--a consensus conference report. Chest 1999;116:521-34. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597-619. Loutfi S. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care Med 2015;doi: 10.1164/rccm.201412-2224CI. Nardi J, Prigent H, Adala A, et al. Nocturnal oximetry and transcutaneous carbon dioxide in home-ventilated neuromuscular patients. Respir Care 2012;57:1425-30. Ogna A, Quera Salva MA, Prigent H, et al. Nocturnal hypoventilation in neuromuscular disease: prevalence according to different definitions issued from the literature. Sleep & breathing = Schlaf & Atmung 2015. Raphael JC, Chevret S, Chastang C, Bouvet F. Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet 1994;343:1600-4. Aarrestad S, Tollefsen E, Kleiven AL, Qvarfort M, Janssens JP, Skjonsberg OH. Validity of transcutaneous PCO2 in monitoring chronic hypoventilation treated with non-invasive ventilation. Respir Med 2016;112:112-8.
15 Page 15 of 17
9. FIGURES: Figure 1: prevalence of nocturnal hypoventilation, according to the different definitions [AASM]: TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes; [Ward]: peak TcCO2 ≥49 mmHg; [Simonds]: mean TcCO2 >50 mmHg
Figure 2: cumulative incidence of the study outcomes over the follow-up period
Figure 3: cumulative incidence of ventilation, according to [AASM] (left panel) and [Ward] definition (right panel). [AASM]: TcCO2 >55 mmHg for ≥10 minutes or increase in TcCO2 ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 minutes; [Ward]: peak TcCO2 ≥49 mmHg
16 Page 16 of 17
8. TABLES: Table 1: characteristics of the study population and capno-oximetry Characteristic Women (n, %)
70 (56.4)
Age (y)
39 [31 ;55]
Age of first symptoms (y)
17 [10 ;41]
Respiratory parameters VC sitting (%pred)
61 [43 ;82]
VC supine (%pred)
54 [34 ;73]
PI max (cmH2O)
42 [28 ;62]
PE max (cmH2O)
33 [22 ;46]
Daytime blood gases pH
7.41 [7.39 ;7.42]
PaCO2 (mmHg)
39.9 [37.8 ;42.4]
PaO2 (mmHg)
78.0 [69.8 ;94.5]
Bicarbonates (mmol/l)
25.2 [23.6 ;26.2]
Total CO2 (mmol/l)
26.5 [24.9 ;27.4]
Nocturnal Capno-Oximetry Duration of the recording (min)
481 [468 ;551]
Oxygen Desaturation Index (no./h)
5 [2 ;12.2]
Mean Oxygen Saturation (%)
96 [94 ;97]
Mean nocturnal TcCO2 (mmHg)
42.8 [39.6 ;45.5]
Max nocturnal TcCO2 (mmHg)
48.4 [44.2 ;51.0]
VC: vital capacity; %pred: percentage of the predicted value; PI max: maximal inspiratory pressure; PE max: maximal expiratory pressure; PaCO2: partial arterial pressure of carbon dioxide (CO2); PaO2: partial arterial oxygen pressure; TcCO2: transcutaneous measure of CO2 Values are expressed as median [IQR] or number of patients (%).
17 Page 17 of 17