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Pacing the Diaphragm in Infants
EDITORIALS
Pacing the Diaphragm in Infants William W. L. Glenn, M.D. In this issue of The Annuls (p 323), Ilbawi and associates report their success in treating hypoventilation of central origin in 8 infants by pacing the diaphragm for a followup of 6 months to 8 years. In 7 infants the condition was congenital and in the other, it was due to respiratory muscle paralysis secondary to trauma. The authors attribute their success to careful patient selection, an innovative surgical technique for implanting the pacemaker, and strict adherence to a pacing program they believed to be safe. Undoubtedly, cooperation of a well-informed and understanding family contributed to the continued success of the pacing program after the infants were discharged from the hospital. Specifics on the electrical parameters used to pace the diaphragm and the physiological data with reference to diaphragmatic function in infants are lacking, though some of this information was provided by the same group [l]in an earlier report. The Chicago group’s success in pacing the diaphragm to treat central alveolar hypoventilation of congenital origin (CCAH) is noteworthy, particularly in view of the extremely poor prognosis for this condition in infants treated by conventional methods of pharmacological or mechanical ventilatory support [2, 31. The syndrome, when recognized in infants, is characterized by cyanosis at birth, hypoventilation predominantly during nonrapid eye movement sleep, and a decreased responsiveness of the central chemoreceptors to hypercapnia [3,4]. Other anomalies of the autonomic nervous system may be present and may complicate management [5]. Although the syndrome was previously considered rare, the first case known to me being reported by Mellins and associates [4] in 1970, a current review of the literature and of the Diaphragm Pacemaker Registry maintained at Yale University shows that CCAH is being diagnosed more and more frequently. Its prevalence has not been determined, but evidently it is greater than was suspected when the syndrome was first described. Of the 112 patients listed in the Diaphragm Pacemaker Registry who have had pacemakers implanted because of central alveolar hypoventilation without respiratory muscle paralysis, 23 (21%)entered with the diagnosis of CCAH. Their average age was 9.3 months at the start of pacing (range, 2 to 40 months). Ventilation was supported by pacing for 2 months to 10 years (mean, 30 months); the patient who was paced for 10 years had been paced since the age of 5 months. In 7 patients (27%) in our clinic with central alveolar hypoventilation without respiratory muscle paralysis, none of whom were infants, no cause for hypoventilation could be identified. It is quite possible that some had had CCAH in infancy that remained undiagnosed but became symptomatic when metabolic demands were increased by growth. (In retroFrom the Department of Surgery, Yale University School of Medicine, 333 Cedar St, Box 3333, New Haven, CT 06510.
319
spect, it is possible the first individual with central alveolar hypoventilation whom we treated successfully by prolonged diaphragm pacing may have been such a patient [6].) In addition, there is evidence that in at least some cases of sudden infant death syndrome (SIDS), the mechanism of death is a defect in the regulation of alveolar ventilation during sleep. One group [7] found that the ventilatory response to carbon dioxide breathing during quiet sleep was impaired in infants who had had previous episodes of prolonged sleep apnea. Others [8] reported that in more than half of the victims of SIDS, there is postmortem evidence of antecedent chronic hypoventilation and hypoxemia. Any infant who has had episodes of apnea should be carefully studied for deficit ventilatory responses to hypercapnia and to hypoxia. The authors have confirmed in infants the effectiveness of pacing the diaphragm for the treatment of central alveolar hypoventilation. I take exception to their preference for fixation of the unipolar electrode to itself, as it thus completely encircles the nerve. The inevitable formation of scar tissue within the confines of the electrode may constrict and prevent normal growth of the nerve, resulting eventually in incomplete innervation of the diaphragm muscle. The unipolar electrode was designed to replace the bipolar neural electrode to avoid having to encircle the phrenic nerve, as well as to facilitate insertion [9]. Placement and fixation of the unipolar electrode behind the phrenic nerve without encirclement has, I believe, been a major factor for success in the long-term pacing of the diaphragm [lo]. There has been considerable concern that electrical stimulation by an electrode placed in direct contact with the phrenic nerve for a prolonged period might damage that nerve. Extensive experimentation in our laboratory has failed to identify injury to the nerve stimulated for pacing the diaphragm that was related solely to the electrical stimulus (111. Reported injury to the nerve has been attributed to operative placement of the neural cuff, malalignment or displacement of the cuff, or infection [12,13]. Another concern in pacing the diaphragm is possible injury to the diaphragm muscle by electrical stimulation. It has been demonstrated experimentally that highfrequency electrical stimulation at 20 Hz (pulse interval, 40 msec) applied to the phrenic nerve for prolonged periods at a pulse train repetition (respiratory) rate of 20 per minute irreparably damages diaphragm muscle [ 14, 151. The authors (161 demonstrated in an earlier report that to adequately ventilate the infant, they had to pace both hemidiaphragms simultaneously. They point out in the current study that to avoid fatigue, they limited pacing to 12 continuous hours and then, presumably after a period of rest, resumed pacing for a total of 16 to 18 hours daily. (When the patient is older, and provided the diaphragm has not been damaged by high-frequency stimulation, it will be possible to convert the pacing
320 The Annals of Thoracic Surgery Vol 40 No 4 October 1985
schedule to a full-time one using the low-frequency/ slow-respiratory rate combination. This has been done in 2 older children in our series, 1 with severe central hypoventilation-probably congenital-and the other with quadriplegia and respiratory muscle paralysis.)* No complications were attributed to the pacing schedule used by the authors for as long as 8 years (average, 2.4 years). However, they describe a progression in infants of hypoventilation during sleep to awake hypoventilation as well (one instance in the reported series was mentioned), necessitating full-time ventilatory support, which was provided for equal periods by bilateral pacing of the diaphragm and positive-pressure ventilation. Several possible explanations for the evolution to constant hypoventilation are given. In my opinion, constriction of the phrenic nerve by scar tissue and pacing for prolonged periods using high-frequency stimulation and a rapid respiratory rate are the most likely causes. In our own experience with older patients in whom central alveolar hypoventilation was well established and unresponsiveness of the respiratory center to hypercapnia or hypoxia or both was demonstrated, there has been no reversal of the abnormal response after a number of years. It appears from reported cases that respiratory center malfunction in most infants with CCAH is long lasting and that a lifetime commitment to some type of respiratory support system is to be anticipated. That pacing the diaphragm has continued to be effective in 3 of our first 4 adult patients with central alveolar hypoventilation and in the first 2 patients with quadriplegia and total respiratory paralysis for an average of about 15 years bodes well for the long-term success of the method. In the interim, 3 of the 5 have shown some lessening of diaphragmatic function, but in none of these patients were the electrical parameters used for pacing the diaphragm and the operative technique employed ideally suited to preserving diaphragmatic structure and function [lo]. Based on more recent studies, we have modified the operative technique and the pacing parameters. We reduced the stimulus frequency (Hz) by widening the pulse interval and lowered the pulse train repetition (respiratory) rate. With these modifications, the diaphragm muscle’s strength and endurance irnpmved [lq. The employment of radiofrequency transmission of impulses to an implanted radio receiver and electrode assembly, by allowing manual control of the pacing parameters, has made it easy to determine those parameters that would be safe for use in stimulation of neural tissue [MI.Now that most of the basic characteristics of the electrical parameters to stimulate the diaphragm have been identified, it is no longer necessary to continue the clinical use of the cumbersome external radio frequency pacemaker. A programmable, totally implantable, battery-powered pacemaker, which is now undergoing testing in the experimental laboratory, would immeasurably simphfy the application of diaphragm pacing. There is no evidence at present that prolonged direct stimulation of the phrenic nerve causes irreversible dam‘Glenn WWL, Loke ]SO: Unpublished data, 1985
age to either the nerve or the diaphragmatic muscle when it is carried out by techniques of proven safety. It is not unreasonable to expect that even infants with central alveolar hypoventilation who must have ventilatory suppod indefinitely can be managed by pacing the diaphragm.
References 1. Brouillette RT, Ilbawi MN, Hunt CE: Phrenic nerve pacing in infants and children: a review of experience and report on the usefulness of phrenic nerve stimulation studies. J Pediatr 102:32, 1983 2. Newth CJL, Packman S, Bachand RT Jr: Response to almitrine bismesylate in a child with a central alveolar hypoventilation syndrome. Eur J Respir Dis [Suppl126]64:303,1983 3. Guilleminault C, McQuitty J, Ariagno RL, et al: Congenital central alveolar hypoventilation syndrome in six infants. Pediatrics 70684, 1982 4. Mellins RB, Balfour HH Jr, Turino GM, Winters RW: Failure of automatic control of ventilation (Ondine‘s curse). Medicine 49:487, 1970 5. Haddad GG, Mazza NM, Defendini R, et al: Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 57:517,1978 6. Judson JP, Glenn WWL: Radio-frequency electrophrenic respiration: long-term application to a patient with primary hypoventilation. JAMA 203:1033, 1968 7. Shannon DC, Kelly DH, OConnell K Abnormal regulation of ventilation in infants at risk for sudden-infant-deathsyndrome. N Engl J Med 297:747,1977 8. Naeye RL: The sudden infant death syndrome: a review of recent advances. Arch Pathol Lab Med 101:165,1977 9. Glenn WWL, Holcomb WG, Hogan JF, et al: Long-term stimulation of the phrenic nerve for diaphragm pacing. In Hambrecht FT, Reswick JB (eds): Functional Electrical Stimulation: Application in Neural Prostheses. New York, Dekker, 1977, pp 97-112 10. Glenn WWL, Hogan JF, Phelps ML: Ventilatory support of the quadriplegic patient with respiratory paralysis by diaphragm pacing. Surg Clin North Am 60:1055,1980 11. Kim JH, Manuelidis EE, Glenn WWL, et al: Light and electron microscopic studies of phrenic nerves after long-term electrical stimulation. J Neurosurg 58:84,1983 12. Kim JH,Manuelidis EE, Glenn WWL, Kaneyuki T Diaphragm pacing: histopathological changes in the phrenic nerve following long-term electrical stimulation. J Thorac Cardiovasc Surg 72502, 1976 13. Shaw RK,Glenn WWL, Hogan JF, Phelps ML: Electrophysiological evaluation of phrenic nerve function in candidates for diaphragm pacing. J Neurosurg 5335, 1980 14. Oda T, Glenn WWL, Fukuda Y, et al: Evaluation of electrical parameters for diaphragm pacing: an experimental study. J Surg Res 30:142,1981 15. Ciesielski TE, Fukuda Y, Glenn WWL, et al: Response of the diaphragm muscle to electrical stimulation of the phrenic nerve: a histochemical and ultrastructural study. J Neurosurg 58:92, 1983 16. Hunt CE, Matalon SY, Thompson TR, et al: Central hypoventilation syndrome: experience with bilateral phrenic nerve pacing in 3 neonates. Am Rev Respir Dis 118:23,1978 17. Glenn WWL, Hogan JF, Loke JSO, et al: Ventilatory support by pacing of the conditioned diaphragm in quadriplegia. N Engl J Med 310:1150, 1984 18. Eisenberg L, Mauro A, Glenn WWL, Hageman JH: Radiofrequency stimulation: a research and clinical tool. Science 147:578,1965
Pacing the Diaphragm in Infants William W. L. Glenn, M.D. In this issue of The Annuls (p 323), Ilbawi and associates report their success in treating hypoventilation of central origin in 8 infants by pacing the diaphragm for a followup of 6 months to 8 years. In 7 infants the condition was congenital and in the other, it was due to respiratory muscle paralysis secondary to trauma. The authors attribute their success to careful patient selection, an innovative surgical technique for implanting the pacemaker, and strict adherence to a pacing program they believed to be safe. Undoubtedly, cooperation of a well-informed and understanding family contributed to the continued success of the pacing program after the infants were discharged from the hospital. Specifics on the electrical parameters used to pace the diaphragm and the physiological data with reference to diaphragmatic function in infants are lacking, though some of this information was provided by the same group [l]in an earlier report. The Chicago group’s success in pacing the diaphragm to treat central alveolar hypoventilation of congenital origin (CCAH) is noteworthy, particularly in view of the extremely poor prognosis for this condition in infants treated by conventional methods of pharmacological or mechanical ventilatory support [2, 31. The syndrome, when recognized in infants, is characterized by cyanosis at birth, hypoventilation predominantly during nonrapid eye movement sleep, and a decreased responsiveness of the central chemoreceptors to hypercapnia [3,4]. Other anomalies of the autonomic nervous system may be present and may complicate management [5]. Although the syndrome was previously considered rare, the first case known to me being reported by Mellins and associates [4] in 1970, a current review of the literature and of the Diaphragm Pacemaker Registry maintained at Yale University shows that CCAH is being diagnosed more and more frequently. Its prevalence has not been determined, but evidently it is greater than was suspected when the syndrome was first described. Of the 112 patients listed in the Diaphragm Pacemaker Registry who have had pacemakers implanted because of central alveolar hypoventilation without respiratory muscle paralysis, 23 (21%)entered with the diagnosis of CCAH. Their average age was 9.3 months at the start of pacing (range, 2 to 40 months). Ventilation was supported by pacing for 2 months to 10 years (mean, 30 months); the patient who was paced for 10 years had been paced since the age of 5 months. In 7 patients (27%) in our clinic with central alveolar hypoventilation without respiratory muscle paralysis, none of whom were infants, no cause for hypoventilation could be identified. It is quite possible that some had had CCAH in infancy that remained undiagnosed but became symptomatic when metabolic demands were increased by growth. (In retroFrom the Department of Surgery, Yale University School of Medicine, 333 Cedar St, Box 3333, New Haven, CT 06510.
319
spect, it is possible the first individual with central alveolar hypoventilation whom we treated successfully by prolonged diaphragm pacing may have been such a patient [6].) In addition, there is evidence that in at least some cases of sudden infant death syndrome (SIDS), the mechanism of death is a defect in the regulation of alveolar ventilation during sleep. One group [7] found that the ventilatory response to carbon dioxide breathing during quiet sleep was impaired in infants who had had previous episodes of prolonged sleep apnea. Others [8] reported that in more than half of the victims of SIDS, there is postmortem evidence of antecedent chronic hypoventilation and hypoxemia. Any infant who has had episodes of apnea should be carefully studied for deficit ventilatory responses to hypercapnia and to hypoxia. The authors have confirmed in infants the effectiveness of pacing the diaphragm for the treatment of central alveolar hypoventilation. I take exception to their preference for fixation of the unipolar electrode to itself, as it thus completely encircles the nerve. The inevitable formation of scar tissue within the confines of the electrode may constrict and prevent normal growth of the nerve, resulting eventually in incomplete innervation of the diaphragm muscle. The unipolar electrode was designed to replace the bipolar neural electrode to avoid having to encircle the phrenic nerve, as well as to facilitate insertion [9]. Placement and fixation of the unipolar electrode behind the phrenic nerve without encirclement has, I believe, been a major factor for success in the long-term pacing of the diaphragm [lo]. There has been considerable concern that electrical stimulation by an electrode placed in direct contact with the phrenic nerve for a prolonged period might damage that nerve. Extensive experimentation in our laboratory has failed to identify injury to the nerve stimulated for pacing the diaphragm that was related solely to the electrical stimulus (111. Reported injury to the nerve has been attributed to operative placement of the neural cuff, malalignment or displacement of the cuff, or infection [12,13]. Another concern in pacing the diaphragm is possible injury to the diaphragm muscle by electrical stimulation. It has been demonstrated experimentally that highfrequency electrical stimulation at 20 Hz (pulse interval, 40 msec) applied to the phrenic nerve for prolonged periods at a pulse train repetition (respiratory) rate of 20 per minute irreparably damages diaphragm muscle [ 14, 151. The authors (161 demonstrated in an earlier report that to adequately ventilate the infant, they had to pace both hemidiaphragms simultaneously. They point out in the current study that to avoid fatigue, they limited pacing to 12 continuous hours and then, presumably after a period of rest, resumed pacing for a total of 16 to 18 hours daily. (When the patient is older, and provided the diaphragm has not been damaged by high-frequency stimulation, it will be possible to convert the pacing
320 The Annals of Thoracic Surgery Vol 40 No 4 October 1985
schedule to a full-time one using the low-frequency/ slow-respiratory rate combination. This has been done in 2 older children in our series, 1 with severe central hypoventilation-probably congenital-and the other with quadriplegia and respiratory muscle paralysis.)* No complications were attributed to the pacing schedule used by the authors for as long as 8 years (average, 2.4 years). However, they describe a progression in infants of hypoventilation during sleep to awake hypoventilation as well (one instance in the reported series was mentioned), necessitating full-time ventilatory support, which was provided for equal periods by bilateral pacing of the diaphragm and positive-pressure ventilation. Several possible explanations for the evolution to constant hypoventilation are given. In my opinion, constriction of the phrenic nerve by scar tissue and pacing for prolonged periods using high-frequency stimulation and a rapid respiratory rate are the most likely causes. In our own experience with older patients in whom central alveolar hypoventilation was well established and unresponsiveness of the respiratory center to hypercapnia or hypoxia or both was demonstrated, there has been no reversal of the abnormal response after a number of years. It appears from reported cases that respiratory center malfunction in most infants with CCAH is long lasting and that a lifetime commitment to some type of respiratory support system is to be anticipated. That pacing the diaphragm has continued to be effective in 3 of our first 4 adult patients with central alveolar hypoventilation and in the first 2 patients with quadriplegia and total respiratory paralysis for an average of about 15 years bodes well for the long-term success of the method. In the interim, 3 of the 5 have shown some lessening of diaphragmatic function, but in none of these patients were the electrical parameters used for pacing the diaphragm and the operative technique employed ideally suited to preserving diaphragmatic structure and function [lo]. Based on more recent studies, we have modified the operative technique and the pacing parameters. We reduced the stimulus frequency (Hz) by widening the pulse interval and lowered the pulse train repetition (respiratory) rate. With these modifications, the diaphragm muscle’s strength and endurance irnpmved [lq. The employment of radiofrequency transmission of impulses to an implanted radio receiver and electrode assembly, by allowing manual control of the pacing parameters, has made it easy to determine those parameters that would be safe for use in stimulation of neural tissue [MI.Now that most of the basic characteristics of the electrical parameters to stimulate the diaphragm have been identified, it is no longer necessary to continue the clinical use of the cumbersome external radio frequency pacemaker. A programmable, totally implantable, battery-powered pacemaker, which is now undergoing testing in the experimental laboratory, would immeasurably simphfy the application of diaphragm pacing. There is no evidence at present that prolonged direct stimulation of the phrenic nerve causes irreversible dam‘Glenn WWL, Loke ]SO: Unpublished data, 1985
age to either the nerve or the diaphragmatic muscle when it is carried out by techniques of proven safety. It is not unreasonable to expect that even infants with central alveolar hypoventilation who must have ventilatory suppod indefinitely can be managed by pacing the diaphragm.
References 1. Brouillette RT, Ilbawi MN, Hunt CE: Phrenic nerve pacing in infants and children: a review of experience and report on the usefulness of phrenic nerve stimulation studies. J Pediatr 102:32, 1983 2. Newth CJL, Packman S, Bachand RT Jr: Response to almitrine bismesylate in a child with a central alveolar hypoventilation syndrome. Eur J Respir Dis [Suppl126]64:303,1983 3. Guilleminault C, McQuitty J, Ariagno RL, et al: Congenital central alveolar hypoventilation syndrome in six infants. Pediatrics 70684, 1982 4. Mellins RB, Balfour HH Jr, Turino GM, Winters RW: Failure of automatic control of ventilation (Ondine‘s curse). Medicine 49:487, 1970 5. Haddad GG, Mazza NM, Defendini R, et al: Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 57:517,1978 6. Judson JP, Glenn WWL: Radio-frequency electrophrenic respiration: long-term application to a patient with primary hypoventilation. JAMA 203:1033, 1968 7. Shannon DC, Kelly DH, OConnell K Abnormal regulation of ventilation in infants at risk for sudden-infant-deathsyndrome. N Engl J Med 297:747,1977 8. Naeye RL: The sudden infant death syndrome: a review of recent advances. Arch Pathol Lab Med 101:165,1977 9. Glenn WWL, Holcomb WG, Hogan JF, et al: Long-term stimulation of the phrenic nerve for diaphragm pacing. In Hambrecht FT, Reswick JB (eds): Functional Electrical Stimulation: Application in Neural Prostheses. New York, Dekker, 1977, pp 97-112 10. Glenn WWL, Hogan JF, Phelps ML: Ventilatory support of the quadriplegic patient with respiratory paralysis by diaphragm pacing. Surg Clin North Am 60:1055,1980 11. Kim JH, Manuelidis EE, Glenn WWL, et al: Light and electron microscopic studies of phrenic nerves after long-term electrical stimulation. J Neurosurg 58:84,1983 12. Kim JH,Manuelidis EE, Glenn WWL, Kaneyuki T Diaphragm pacing: histopathological changes in the phrenic nerve following long-term electrical stimulation. J Thorac Cardiovasc Surg 72502, 1976 13. Shaw RK,Glenn WWL, Hogan JF, Phelps ML: Electrophysiological evaluation of phrenic nerve function in candidates for diaphragm pacing. J Neurosurg 5335, 1980 14. Oda T, Glenn WWL, Fukuda Y, et al: Evaluation of electrical parameters for diaphragm pacing: an experimental study. J Surg Res 30:142,1981 15. Ciesielski TE, Fukuda Y, Glenn WWL, et al: Response of the diaphragm muscle to electrical stimulation of the phrenic nerve: a histochemical and ultrastructural study. J Neurosurg 58:92, 1983 16. Hunt CE, Matalon SY, Thompson TR, et al: Central hypoventilation syndrome: experience with bilateral phrenic nerve pacing in 3 neonates. Am Rev Respir Dis 118:23,1978 17. Glenn WWL, Hogan JF, Loke JSO, et al: Ventilatory support by pacing of the conditioned diaphragm in quadriplegia. N Engl J Med 310:1150, 1984 18. Eisenberg L, Mauro A, Glenn WWL, Hageman JH: Radiofrequency stimulation: a research and clinical tool. Science 147:578,1965