Diaphragm pacing in patients with amyotrophic lateral sclerosis

Abstract

1 DiPALS Writing Committee; DiPALS Study Group Collaborators; McDermott CJ, Bradburn MJ, Maguire C, et al. Safety and effi cacy of diaphragm pacing in patients with respiratory insuffi ciency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. Lancet Neurol 2015; 14: 883–92. 2 Elmo M, Onders R, Miller R. Multi-center diaphragm pacing post FDA approval study enrollment complete: Favorable procedural success, interim safety and survival fi ndings. Amyotroph Lateral Scler Frontotemporal Degener 2015; 16 (suppl 1): 29. 3 US Food and Drug Administration. Summary of safety and probable benefi t (SSPB). 2011. http://www.accessdata.fda.gov/cdrh_ docs/ pdf10/H100006b.pdf (accessed April 11, 2015). 4 Lepore AC, Tolmie C, O’Donnell J, et al. Peripheral hyperstimulation alters site of disease onset and course in SOD1 rats. Neurobiol Dis 2010; 39: 252–64. with diaphragm pacing (median survival of 21·2 months in 60 patients from 11 centres). These fi ndings are similar to those presented to the Food and Drug Administration that led to the approval for use of diaphragm pacing under Humanitarian Device Exemption (median survival of 19·7 months in the fi rst pivotal study, 85 patients from eight centres). McDermott and colleagues raised the safety concern that the surgery for diaphragm pacing might have triggered worsening of patients with amyotrophic lateral sclerosis. 30 day mortality was 0 of 37 patients in the DiPALS study, 0 of 106 in the Humanitarian Device Exemption study, and three of 54 in the postapproval study. 90 day mortality was one of 37 patients in the DiPALS study, three of 106 in the Humanitarian Device Exemption study, and eight of 60 in the post-approval study. Thus, no increased mortality from surgery was apparent in the DiPALS study. The rate of change of the ALS Functional Rating Scale-Revised (ALSFRS-R) in the Humanitarian Device Exemption study was 0·80 points per month 3 months before implantation, and 0·73 per month 4 months after implantation. None of these data support the hypothesis that surgery made patients worse. The DiPALS investigators questioned whether ongoing stimulation of the diaphragm might be harmful. Poor outcomes were observed in the SOD1 rat model of amyotrophic lateral sclerosis when high stimulation rates (33 Hz) were used. The DiPALS data showed no association between survival and use of pacing (HR 1·00 per additional hour use, 95% CI –0·92 to 1·09, p=0·92), and patients tolerated stimulation well, with only two patients discontinuing pacing. To us, the reported survival diff erence seemed to hinge on the lack of use of non-invasive ventilation in roughly 30% of study patients. We believe further studies are needed to clarify Diaphragm pacing in patients with amyotrophic lateral sclerosis