The history of pacing the diaphragm is not new. The earliest record of phrenic stimulation for the treatment of asphyxia was reported in 1783. In the mid-1850s, French neurologists also proposed such an idea, but it was Hugo Wilhelm von Ziemssen who performed the first diaphragmatic pacing on a young female patient who had asphyxiated on charcoal vapor. Several decades later, Duchenne also commended the benefits of diaphragmatic stimulation. Diaphragmatic stimulation did not gain any momentum because of the crude nature of surgery and lack of appropriate anesthesia. The technique was revived about a century later by Sarnoff and colleagues at Harvard, where they paced the phrenic nerve in dogs. Later, they applied the technique to a young child with complete respiratory paralysis following an intracranial aneurysm rupture. However, the true beginnings of diaphragmatic pacing started in the 1860s and 70s. The father of modern diaphragm pacing is Dr William W L Glenn from Yale University, who showed that the technique was not only practical but could be used clinically for the treatment for several medical disorders. With advances in technology, more refined and flexible electrodes were developed, and the thoracoscopic method of implantation became practical. [1, 2, 3, 4, 5]
There are 3 commercially available devices that can stimulate the diaphragm—namely, the Synapse Biomedical NeuRx; the Mark IV Breathing Pacemaker, made by Avery Biomedical Devices; and the Atrotech OY’s Atrostim PNS. The Avery and the Synapse devices are available in the United States, and the Atrotech device is available only in Europe. The Synapse NeuRx DPS received FDA approval in 2011 for humanitarian use in patients 21 years or older with amyotrophic lateral sclerosis (ALS), and the cost may not be reimbursed by Medicaid or Medicare services. The Avery Mark IV Breathing Pacemaker received full premarket approval by the FDA in 1987 and is reimbursed by Medicaid and Medicare services. A key difference between the two is that the Mark IV Breathing Pacemaker stimulates the phrenic nerve and the NeuRx DPS stimulates the diaphragm. [6, 7]
All currently available systems involve an external transmitter and an implanted receiver, but fully implantable diaphragmatic pacing systems are being developed. The current pacing systems are more affordable and easier to place than the earlier systems. [5, 10]
Diaphragmatic pacing should be considered in the following patients:
Diaphragm pacing is performed to provide ventilatory support in 2 main clinical scenarios:
Central alveolar ventilation, or what is better known as sleep apnea
High spinal cord paralysis in which the drive for respiration is still present but the injury to the spinal cord prevents stimulation from the phrenic nerves
Another, albeit rare, use of diaphragm pacing is to treat patients with intractable hiccups.  The remaining group of patients in whom diaphragm pacing has been used consists of those with severe COPD. In these individuals, the hypoxic stimulation is diminished by administration of any amount of oxygen. 
Diaphragm pacing is contraindicated for patients in whom the phrenic nerve is not functional. Such patients include those with severe traumatic injury to the nerve, those with nerve tumors, and most of those with neuropathies. In addition, diaphragm pacing is contraindicated for patients with conditions in which the diaphragm itself is not functional.
Compared with positive-pressure ventilation, diaphragm pacing has a number of advantages. One major advantage is that it allows a greater degree of independence. With diaphragm pacing, the patient is no longer isolated in a room, attached to a mechanical ventilator with an uncomfortable tube down the upper airways. Patients with central hypoventilation may be able to ambulate, go to work, travel, and perform most daily living activities. Portable diaphragmatic pacemakers are available that can be used for ambulatory monitoring of heart rate and rhythm.
Another major advantage is that diaphragm pacing affords the patient the ability to speak, which is impossible with an endotracheal tube in place. Once diaphragm pacing has been performed, the tracheostomy stoma can be plugged and speech resumed. Speech capability made possible by diaphragm pacing is particularly important to patients who are quadriplegic and on a ventilator. [16, 17, 18, 19] In addition, diaphragm pacing does not result in tracheal injury, tracheomalacia, tracheal stenosis, subglottic stenosis, tracheoesophageal fistula, or tracheitis.
Furthermore, the extremely irritating copious secretions seen during mechanical ventilation are avoided. Patients on a ventilator are always at risk for death. The tubing may become kinked, coiled, obstructed, or even disconnected, and the tracheostomy site may become plugged. 
Studies have shown that diaphragm pacing is effective and helps support ventilation in specific patient populations. Diaphragmatic pacing can provide independence from a mechanical ventilator and can help patients communicate and have a better quality of life. However, long-term studies are still needed; the majority of studies published are retrospective studies or case reports. [21, 22] Some studies have reported that patients can be paced for up to 20 years without much negative sequelae; however, the data have been difficult to interpret because of heterogeneity of methodology for follow-up. It should also be mentioned that a trial involving the NeuTx DPS system pacer for patients with ALS was halted and there is concern that this device may actually be causing harm. [4, 5, 13, 17, 18, 19, 23, 24, 25, 26, 27, 28, 29, 30]
Elefteriades JA. The diaphragm: dysfunction and induced pacing. Baue AE, Geha AS, Hammond GL, Laks H, Nuanheim K, eds. Glenn’s Thoracic and Cardiovascular Surgery. 6th ed. Stamford, CT: Appleton & Lange; 1996. 623-42.
Elefteriades JA, Quin JA. Pacing of the diaphragm. Shields TW, LoCicero J III, Ponn R, eds. General Thoracic Surgery. 5th ed. Lippincott, Williams & Wilkins: Philadelphia; 2000. 623-36.
Glenn WW. The treatment of respiratory paralysis by diaphragm pacing. Ann Thorac Surg. 1980 Aug. 30(2):106-9. [Medline].
Chen ML, Tablizo MA, Kun S, Keens TG. Diaphragm pacers as a treatment for congenital central hypoventilation syndrome. Expert Rev Med Devices. 2005 Sep. 2(5):577-85. [Medline].
Le Pimpec-Barthes F, Legras A, Arame A, Pricopi C, Boucherie JC, Badia A, et al. Diaphragm pacing: the state of the art. J Thorac Dis. 2016 Apr. 8 (Suppl 4):S376-86. [Medline].
FDA. NEURX DIAPHRAGM PACING SYSTEM (DPS). FDA Humanitarian Device Exemption. Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H100006. September 28, 2011; Accessed: January 15, 2018.
FDA. DIAPHRAGMATIC PACEMAKER PHRENIC NERVE STIMULATOR. FDA Premarket Approval. Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P860026. January 5, 1987; Accessed: January 15, 2018.
Elefteriades J, Singh M, Tang P, et al. Unilateral diaphragm paralysis: etiology, impact, and natural history. J Cardiovasc Surg (Torino). 2008 Apr. 49(2):289-95. [Medline].
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Thalhofer S, Dorow P. Central sleep apnea. Respiration. 1997. 64(1):2-9. [Medline].
Chervin RD, Guilleminault C. Diaphragm pacing: review and reassessment. Sleep. 1994 Mar. 17(2):176-87. [Medline].
Chervin RD, Guilleminault C. Diaphragm pacing for respiratory insufficiency. J Clin Neurophysiol. 1997 Sep. 14(5):369-77. [Medline].
Kotan D, Kaymak K, Gundogdu AA. Diaphragm pacing system implanted in a patient with ALS. J Back Musculoskelet Rehabil. 2015 Sep 25. [Medline].
Andres DW. Transesophageal diaphragmatic pacing for treatment of persistent hiccups. Anesthesiology. 2005 Feb. 102 (2):483. [Medline].
Glenn WW, Gee JB, Schachter EN. Diaphragm pacing. Application to a patient with chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg. 1978 Feb. 75 (2):273-81. [Medline].
Gater DR Jr, Dolbow D, Tsui B, Gorgey AS. Functional electrical stimulation therapies after spinal cord injury. NeuroRehabilitation. 2011. 28(3):231-48. [Medline].
Khong P, Lazzaro A, Mobbs R. Phrenic nerve stimulation: the Australian experience. J Clin Neurosci. 2010 Feb. 17(2):205-8. [Medline].
DiMarco AF. Phrenic nerve stimulation in patients with spinal cord injury. Respir Physiol Neurobiol. 2009 Nov 30. 169(2):200-9. [Medline].
Layachi L, Georges M, Gonzalez-Bermejo J, Brun AL, Similowski T, Morelot-Panzini C. Diaphragm pacing failure secondary to deteriorated chest wall mechanics: When a good diaphragm does not suffice to take a good breath in. Respir Med Case Rep. 2015. 15:20-3. [Medline].
Qureshi A. Diaphragm paralysis. Semin Respir Crit Care Med. 2009 Jun. 30(3):315-20. [Medline].
Brouillette RT, Marzocchi M. Diaphragm pacing: clinical and experimental results. Biol Neonate. 1994. 65(3-4):265-71. [Medline].
Bach JR, O’Connor K. Electrophrenic ventilation: a different perspective. J Am Paraplegia Soc. 1991 Jan. 14(1):9-17. [Medline].
Nandra KS, Harari M, Price TP, Greaney PJ, Weinstein MS. Successful Reinnervation of the Diaphragm After Intercostal to Phrenic Nerve Neurotization in Patients With High Spinal Cord Injury. Ann Plast Surg. 2017 Aug. 79 (2):180-182. [Medline].
Onders RP, Markowitz A, Ho VP, Hardacre J, Novitsky Y, Towe C, et al. Completed FDA feasibility trial of surgically placed temporary diaphragm pacing electrodes: A promising option to prevent and treat respiratory failure. Am J Surg. 2017 Nov 11. [Medline].
Şanlı A, Şengün IŞ, Karaçam V, Alpaydın AÖ, Tertemiz KC, Özalevli S, et al. Preoperative parameters and their prognostic value in amyotrophic lateral sclerosis patients undergoing implantation of a diaphragm pacing stimulation system. Ann Indian Acad Neurol. 2017 Jan-Mar. 20 (1):51-54. [Medline].
Onders RP, Elmo M, Kaplan C, Katirji B, Schilz R. Extended use of diaphragm pacing in patients with unilateral or bilateral diaphragm dysfunction: a new therapeutic option. Surgery. 2014 Oct. 156 (4):776-84. [Medline].
Posluszny JA Jr, Onders R, Kerwin AJ, Weinstein MS, Stein DM, Knight J, et al. Multicenter review of diaphragm pacing in spinal cord injury: successful not only in weaning from ventilators but also in bridging to independent respiration. J Trauma Acute Care Surg. 2014 Feb. 76 (2):303-9; discussion 309-10. [Medline].
DiPALS Writing Committee., DiPALS Study Group Collaborators. Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2015 Sep. 14 (9):883-892. [Medline].
Diep B, Wang A, Kun S, McComb JG, Shaul DB, Shin CE, et al. Diaphragm Pacing without Tracheostomy in Congenital Central Hypoventilation Syndrome Patients. Respiration. 2015. 89 (6):534-8. [Medline].
Gonzalez-Bermejo J, Morélot-Panzini C, Tanguy ML, Meininger V, Pradat PF, Lenglet T, et al. Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial. Lancet Neurol. 2016 Nov. 15 (12):1217-1227. [Medline].
Shabir Bhimji, MD, PhD Cardiothoracic and Vascular Surgeon, Saudi Arabia and Middle East Hospitals
Disclosure: Nothing to disclose.
John J Oppenheimer, MD Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA
John J Oppenheimer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, New Jersey Allergy, Asthma and Immunology society
Disclosure: Received research grant from: quintiles, PRA, ICON, Novartis: Adjudication<br/>Received consulting fee from AZ for consulting; Received consulting fee from Glaxo, Myelin, Meda for consulting; Received grant/research funds from Glaxo for independent contractor; Received consulting fee from Merck for consulting; Received honoraria from Annals of Allergy Asthma Immunology for none; Partner received honoraria from ABAI for none. for: Atlantic Health System.
Guy W Soo Hoo, MD, MPH Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Medical Intensive Care Unit, Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, Veteran Affairs Greater Los Angeles Healthcare System
Guy W Soo Hoo, MD, MPH is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society, Society of Critical Care Medicine, California Thoracic Society, American Association for Respiratory Care
Disclosure: Nothing to disclose.
Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women’s Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine
Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society
Disclosure: Nothing to disclose.
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