Jésus Gonzalez-Bermejo1, Capucine Morélot-Panzini2, Marie-Laure Tanguy3, Vincent Meininger4, Pierre-François Pradat5, Timothée Lenglet4, Gaëlle Bruneteau6, Nadine Le Forestier4, Philippe Couratier7, Nathalie Guy8, Claude Desnuelle9, Hélène Prigent10, Christophe Perrin11, Valérie Attali12, Catherine Fargeot13, Marie-Cécile Nierat14, Catherine Royer15, Fabrice Ménégaux16, François Salachas4, Thomas Similowski2. 1. Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France. Electronic address: jesus.gonzalez@psl.aphp.fr. 2. Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France. 3. AP-HP, Groupe Hospitalier Pitié Salpêtrière Charles Foix, Unité de Recherche Clinique, Paris, France. 4. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France. 5. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France. 6. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Centre de Référence Maladies Rares SLA, Département des Maladies du Système Nerveux, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moëlle Epinière, ICM, Paris, France. 7. CHU Limoges, Centre de Compétence SLA, Limoges, France. 8. CHU Gabriel Montpied, Service de Neurologie, Clermont-Ferrand, France; Faculté de Chirurgie Dentaire, Neuro-Dol, INSERM U1107, Douleur Trigéminale et Migraine, Clermont-Ferrand, France. 9. Hôpital Pasteur 2, Centre de Référence SLA, Nice, France. 10. AP-HP, GHU Paris Ouest-site Raymond Poincaré-Service de Physiologie et d'Explorations Fonctionnelles, Garches, France. 11. CH de Cannes, Service de Pneumologie, Cannes, France. 12. Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpêtrière Charles Foix, Service des Pathologies du Sommeil (Département "R3S"), Paris, France. 13. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service Pharmacie UFDMS, Paris, France. 14. Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France. 15. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Département d'Anesthésie et Réanimation, Paris, France. 16. AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Chirurgie Viscérale, Paris, France.
Abstract
BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation. METHODS: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088. FINDINGS:Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported. INTERPRETATION:Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement. FUNDING: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.
RCT Entities:
BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation. METHODS: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088. FINDINGS: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported. INTERPRETATION: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement. FUNDING: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.
Authors: Nicolas Kahn; Laura Fregonese; Miriam Barrecheguren; Frits M E Franssen; Aleksandar Grgic; Daniela Gompelmann; Eleni Bibaki; Katerina M Antoniou; Janwillem W H Kocks; Hillary Pinnock; Felix Herth Journal: ERJ Open Res Date: 2017-04-12
Authors: Tanmay S Panchabhai; Eduardo Mireles Cabodevila; Erik P Pioro; Xiaofeng Wang; Xiaozhen Han; Loutfi S Aboussouan Journal: ERJ Open Res Date: 2019-09-25