Laryngeal transplantation in 2005: a review.

There is no good surgical, medical or prosthetic solution to the problems faced by those with a larynx whose function is irreversibly damaged by tumor or trauma. Over the past 10 years, the pace of research designed to establish laryngeal transplantation as a therapeutic option for these persons has increased steadily. The biggest milestone in this field was the world's first true laryngeal transplant performed in Cleveland, Ohio in 1998. The recipient's graft continues to function well, in many respects, even after 7 years. However, it has also highlighted the remaining barriers to full-scale clinical trials. Stimulated by these observations, several groups have accumulated data which point to answers to some of the outstanding questions surrounding functional reinnervation and immunomodulation. This review seeks to outline the progress achieved in this field by 2005 and to point the way forward for laryngeal transplantation research in the 21st century.

Dynamic tissue expansion of the larynx in a canine model.

OBJECTIVES: To test whether staged, progressive, monitored, dynamic tissue expansion is possible in the larynx and to evaluate its effectiveness in dilating and augmenting constricting cicatricial lesions. DESIGN: Animal study. SETTING: Research facility, tertiary care medical center. SUBJECTS: Thirteen dogs, 3 with laryngotracheal stenosis. INTERVENTIONS: Dogs underwent laryngeal splits, tracheostomy, and insertion of inflatable stents. In 7 normal dogs, stents were progressively inflated by air in predetermined increments during 11 days. In 3 normal dogs and 3 with laryngotracheal stenosis, stents were gradually expanded by water. Stents were kept in place for 21 days. After removal, dogs were observed for 25 days. Five died of complications of tracheostomy. MAIN OUTCOME MEASURES: Airway diameter measured by endoscopy before the induction of stenosis, before the laryngeal splitting procedure, after stent removal, and before euthanasia. RESULTS: The lumen increased, then shrank somewhat after stent removal. In 2 surviving dogs with laryngotracheal stenosis and water-expanded stents, the lumen was 82.5% larger than baseline at stent removal and 71.0% larger at euthanasia. In 2 surviving normal dogs with water-expanded stents, lumen size increased by 50.0% at stent removal, and in 1 dog surviving to day 46, it was 17.0% larger. In 5 surviving dogs with air-inflated stents, lumen size was 39.0% larger at stent removal and 8.0% larger at day 46. Histologically, fibrous tissue developed in the gaps between the splayed margins of the laryngeal cartilages. CONCLUSIONS: The larynx may be dynamically expanded. Although the maximal diameter is not maintained, final cross-sectional areas are larger.

Effect of in vitro irradiation of donor larynges on cyclosporine requirements and rejection rates in rat laryngeal transplantation.

Total lymphoid irradiation is an acknowledged adjunctive immunosuppressant in whole organ transplantation in humans and animals. Local irradiation administered for a similar purpose is at best controversial. We evaluated in vitro donor larynx irradiation immediately preceding laryngeal transplantation as an immunomodulator. Each donor larynx was pretreated with 7.34 Gy of radiation in vitro. After transplantation, cyclosporine was administered in doses of 5 mg/kg per day, 2.5 mg/kg per day, and 1 mg/kg per day for trial lengths of 15 days and 30 days. Each of these 6 groups consisted of 10 rats per group. Earlier data have shown cyclosporine dosed at 5 mg/kg per day, without irradiation, administered for 1 month to have varied efficacy. Established histologic criteria were used to determine rejection patterns. All recipient rats survived the 15-day and 30-day trials. In all 10 rats receiving 5 mg/kg per day of cyclosporine for 15 days, the harvested transplanted larynges were viable without evidence of meaningful rejection (mild rejection). In 9 of the 10 rats receiving 5 mg/kg per day of cyclosporine for 30 days, the transplanted larynges displayed no meaningful rejection (mild rejection). In 9 of the 10 rats receiving 2.5 mg/kg per day of cyclosporine for 15 days, the transplanted larynges displayed no meaningful rejection (mild rejection). One rat receiving 2.5 mg/kg per day of cyclosporine for 15 days had a transplanted larynx that displayed moderate rejection. In all 10 rats receiving 2.5 mg/kg per day of cyclosporine for 30 days, the transplanted larynges displayed no meaningful rejection (mild rejection). At 15 days, 5 rats treated with 1 mg/kg per day of cyclosporine displayed mild rejection, 2 displayed moderate rejection, 2 displayed advanced to moderate rejection, and 1 displayed severe rejection. At 30 days, 4 rats treated with 1 mg/kg per day of cyclosporine displayed moderate rejection, 2 displayed advanced to moderate rejection, and 4 displayed severe rejection. We conclude that pretransplantation in vitro irradiation of donor larynges has immunomodulatory effects, allowing reduced cyclosporine immunosuppression with less rejection.

Effect of mechanical reinforcement on stability of the rotary door flap laryngotracheal reconstruction: a canine study.

OBJECTIVE/HYPOTHESIS: The rotary door flap (RDF) laryngotracheal reconstructive procedure uses a 180 degrees rotation of the sternohyoid muscle into a laryngofissure. Despite excellent clinical results, there are concerns of flap inspiratory prolapse. This study examined RDF stability and the efficacy of ancillary materials in providing additional support. METHODS: Seventeen dogs underwent endoscopic induction of subglottic stenosis and delayed RDF reconstruction. Animals received 1) traditional RDF (control), 2) RDF with titanium screen implant, 3) RDF with porous polyethylene implant, or 4) RDF with hydroxyapatite cement (HAC) injection. Four weeks postoperatively the flaps were tested for stability. On qualitative assessment, endoscopic visualization was completed with quiet respiration and then following endotracheal tube occlusion. On quantitative assessment, after animals were killed, the RDF segment was isolated and subjected to negative pressure (maximum pressure, -50 mm Hg). The pressure-causing collapse was measured. RESULTS: In the traditional RDF animals (control), five of six flaps were stable in vivo and with negative pressures. In the titanium screen, porous polyethylene group, and HAC groups, respectively, four of four, three of four, and two of three flaps were stable in vivo and under negative pressure. Flaps that demonstrated instability had granulation, dehiscence, and poor healing. These occurred in 1 of 6 animals in the traditional RDF group and in 2 of 11 animals in the implant groups. In addition, 13 of 24 animals assigned to the implant groups died, compared with 2 of 8 of those in the traditional RDF group. CONCLUSIONS: The RDF is stable and maintains the airway under physiological conditions. Support materials did not improve stability, render flap harvest more difficult, or increase morbidity and mortality.

Evaluating laryngotracheal stenosis in a canine model with virtual bronchoscopy.

We performed a prospective masked animal study to determine whether virtual bronchoscopy, a noninvasive computed tomography technique, can accurately measure upper airway stenosis. Virtual bronchoscopy creates a 3-dimensional endoscopic image from spiral computed tomography data. Laryngotracheal stenosis was endoscopically induced in 18 dogs. The excised larynges were examined by endoscopy, virtual bronchoscopy, and macrodissection. Measurements were made of the anteroposterior (A-P) diameter, the left-right (L-R) diameter, the full length of stenosis in the sagittal plane, and the length of the tightest stenotic segment. Each measurement method was performed independently. All investigators were unaware of measurements made by others. The measurements obtained through virtual bronchoscopy and actual endoscopy were compared to those made at dissection by interclass correlation coefficients (ICCs). Endoscopy was better than virtual bronchoscopy in measuring the A-P diameter (ICC = .79, p < .0001; ICC = .42, p = .01). Both were equally effective in measuring the L-R diameter (ICC = .53, p = .0062; ICC = .52, p = .0064). The endoscopes could not assess the full length of the stenosis, whereas virtual bronchoscopy measured it fairly accurately (ICC = .72, p = .0001). Virtual bronchoscopy relatively accurately measured the length of the tightest stenotic segment (ICC = .68, p = .0002), whereas endoscopy produced measurements in only 11 of 18 larynges, and the measurements were less accurate (ICC = .45, p = .0068). Virtual bronchoscopy can provide good measurements of stenotic lesions in the airway. It is more accurate than actual endoscopy in determining the length of stenosis. It may therefore be useful as an adjunct imaging method in preoperative planning for reconstructive surgery.

Systemic adoptive T-cell immunotherapy in recurrent and metastatic carcinoma of the head and neck: a phase 1 study.

OBJECTIVE: To evaluate the feasibility and toxic effects of systemic adoptive T-cell immunotherapy in patients with unresectable squamous cell carcinoma of the head and neck (SCCHN). DESIGN: Nonrandomized phase 1 clinical trial. SETTING: Academic tertiary care hospital. PATIENTS: Between April 1, 1996, and September 30, 1998, 17 patients with confirmed recurrent and metastatic SCC of the upper aerodigestive tract were enrolled. Two patients did not receive T cells because of poor vaccine response. Fifteen patients were successfully treated with T-cell immunotherapy. INTERVENTION: Patients were vaccinated on the thigh with irradiated autologous tumor cells admixed with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by 3 additional daily injections of GM-CSF at the vaccination site. Eight to 10 days later, tumor cell vaccine-draining inguinal lymph nodes were resected, and lymph node lymphocytes were activated with staphylococcal enterotoxin A and expanded in interleukin 2 in vitro. Resulting cultured cells were infused into patients peripherally on an outpatient basis. RESULTS: Toxic effects of infusion were limited to grade 2 reactions in 3 of 16 treatments. One patient required overnight hospitalization for fever and emesis. Median cell expansion was 37 times (range, 4-416 times), and median cell dose was 7.5 x 10(9) (range, 1.3 x 10(8) to 4.2 x 10(10)). Infused cells were predominantly CD3+ (>97%), being a mixture of CD4+ and CD8+ cells. Three patients demonstrated stabilization of previously progressive disease. Two patients experienced favorable clinical courses after adoptive T-cell transfer, including 1 patient with no evidence of disease 4 years after surgical resection of a vertebral body metastasis. CONCLUSIONS: Adoptive immunotherapy is a technically feasible and safe treatment with low toxicity and may demonstrate therapeutic activity in patients with unresectable SCCHN.

Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck.

BACKGROUND: The current study presents mature results from a Phase III randomized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with resectable American Joint Committee on Cancer Stage III and IV disease. METHODS: One hundred patients were randomized to receive either radiation therapy alone (Arm A) (at a dose of between 66-72 grays [Gy] at 1.8-2 Gy per day) and the identical radiation therapy with concurrent chemotherapy (Arm B) (5-fluorouracil, 1000 mg/m(2)/day, and cisplatin, 20 mg/m(2)/day, both given as continuous intravenous infusions over 4 days beginning on Days 1 and 22 of the radiation therapy). Primary site resection was planned for patients with residual or recurrent local disease. Cervical lymph node dissection was performed for regional persistent disease or recurrence, or if N2-3 disease was present at the time of presentation. RESULTS: After completing all therapy including surgery, 82% of the patients in Arm A and 98% of the patients in Arm B had been rendered disease free (P = 0.02). At a median follow-up of 5 years (range, 3-8 years), the 5-year Kaplan-Meier projections for overall survival for Arm A versus Arm B were 48% versus 50% (P = 0.55). Kaplan-Meier projections for the recurrence free interval were 51% versus 62% (P = 0.04), projections for a distant metastasis free interval were 75% versus 84% (P = 0. 09), projections for overall survival with primary site preservation were 34% versus 42% (P = 0.004), and projections for local control without surgical resection were 45% versus 77% (P < 0.001). Salvage surgery proved to be successful in 63% and 73%, respectively, of the Arm A and Arm B patients with primary site failure. Unrelated death while free of disease occurred in 22% and 32%, respectively, of Arm A and Arm B patients (P = 0.26). CONCLUSIONS: The addition of concurrent chemotherapy to definitive radiation in patients with resectable Stage III and IV squamous cell carcinoma of the head and neck improves the likelihood of disease clearance, a recurrence free interval, and primary site preservation. However, overall survival does not appear to be improved, reflecting both effective surgical salvage after local recurrence and competing causes of death.

Histopathologic study of alternative substances for vocal fold medialization.

This research investigated the histopathologic and migratory properties of injectable alternatives for vocal fold medialization. Thirteen dogs underwent sectioning of the recurrent laryngeal nerve followed by vocal fold injection with 1 of 4 substances: Teflon, autologous fat, silicone suspension, or hydroxyapatite cement. Six months later, the animals were painlessly sacrificed and histopathologic analysis of the larynx and regional lymph nodes was performed. Although regional lymph node migration was noted, Teflon injection resulted in minimal vocal fold inflammatory reaction. Vocal folds injected with autologous fat exhibited persistence of fat at the injection site without significant inflammation or migration. Silicone suspension caused a localized giant cell reaction without regional lymph node migration, and 1 study subject died secondary to acute inflammation with critical respiratory compromise. Hydroxyapatite cement was well tolerated without inflammation or migration. This pilot study indicates that a wide range of possible substances for vocal fold medialization exist. Many of these may produce results superior to those obtained with Teflon and are thus far untested.

Improved canine model for laryngotracheal stenosis.

Laryngotracheal stenosis (LTS) is a serious challenge for the otolaryngologist. Although progress has been made in preventing and treating LTS, more research is required. Existing canine models for LTS incur high mortality and morbidity, require relatively complicated procedures or costly equipment, entail lengthy waiting periods, or have unpredictable results. A simple, reliable, and inexpensive procedure, requiring no tracheotomy, is described for creating a canine model for LTS research. The new improved model is compared with previous models described in the literature. It will be especially useful for short-term studies of subglottic or tracheal stenosis.

Impact of steroids on recovery after uvulopalatopharyngoplasty.

OBJECTIVE: To determine whether perioperative systemic corticosteroid administration can reduce uvulopalatopharyngoplasty (UPPP) postoperative morbidities (e.g., pain, anorexia, sleep disturbance, mouth odor, and fatigue) or reduce narcotic analgesic usage. STUDY DESIGN: A prospective, double-blinded study with random assignment of treatment agent (placebo or corticosteroid). METHODS: From 1995 to 1998, a consecutive sample of 48 adults presenting for elective UPPP surgery alone or in combination with tonsillectomy or septoplasty, or both, were enrolled. Twenty-eight subjects completed the protocol and were equally distributed by random assignment to intramuscular (IM) and intravenous (IV) doses of placebo (saline) or corticosteroid (60 mg methylprednisolone IM and 12 mg dexamethasone IV). Acetaminophen with codeine analgesic was available to both groups as needed. Subjects recorded a diary of symptom severity scores over the first postoperative week relating to eight commonly reported morbidities (1-4 points) and the daily quantity of narcotic consumed. RESULTS: Statistical comparison (Wilcoxon's rank sum test) showed no significant differences between subjects treated with placebo or corticosteroid on postoperative day 1 or 7. Three subjects (21%) in each treatment group reported no postoperative use of narcotic analgesic. CONCLUSIONS: No statistically or clinically significant benefits were derived from perioperative systemic corticosteroid treatment in this sample of 28 adults treated with UPPP alone or in combination with tonsillectomy or septoplasty, or both. Some individuals tolerate post-UPPP discomfort without a narcotic analgesic.

Can topical mitomycin prevent laryngotracheal stenosis?

OBJECTIVES/HYPOTHESIS: Early topical application of mitomycin to a laryngotracheal lesion may prevent or reduce laryngotracheal stenosis (LTS). STUDY DESIGN: Prospective controlled animal study. METHODS: LTS was induced in 60 dogs randomly assigned to four groups. Controls received an immediate topical application of normal saline. The suction-control group received an immediate application of normal saline followed by suction of secretions on day 2. The mitomycin group received immediate application of 0.7 mL mitomycin (0.2 mg/mL). The repeat-mitomycin group received an immediate application of mitomycin and a second application on day 2, after secretions were suctioned. The laryngeal lumens were measured endoscopically at baseline, day 12, and day 21. Animals were euthanatized if stenosis approximated 95% or at day 21. RESULTS: All dogs in the mitomycin groups survived to day 21, compared with 12 in the suction group and only 2 controls. No side effects of mitomycin were observed. At day 21, surviving controls had 85% and 95% stenosis. In the mitomycin group, median stenosis was 27% (interquartile range, 29% to 42%); in the repeat-mitomycin group, 30% (22% to 40%); and in the suction-control group, 84.5% (72.5% to 93.5%). The mitomycin group differed significantly from controls on day 12 (median difference = 85%, 95% CI = 80%-94%, P < .0001) and day 21 (difference = 63.9%, 95% CI = 58%-85%, P = .031). CONCLUSION: A single topical application of mitomycin significantly reduces the severity of LTS in dogs. Reapplication after 2 days does not improve results. Prospective clinical studies are warranted to assess the efficacy in humans.

Vagal stimulation for reciprocal coupling between glottic and upper esophageal sphincter activities in the canine.

Glottic adduction couples with relaxation of the tonically contracted upper esophageal sphincter (UES) to constitute the end point of pharyngeal swallowing. Together with deglutitive laryngeal elevation, this reciprocal relationship contributes to protecting the lungs from aspiration. Degrees of uncoordination between glottic and upper esophageal sphincters can be seen under diverse circumstances of neurologic damage such as stroke, gastroesophageal reflux, and in the growing elderly population presenting with weaker musculature. We hypothesized that reciprocal coupling between glottic closure and UES relaxation may be artificially reestablished through vagal stimulation if the appropriate neural centers and their leading pathways remain capable of exciting a critical number of motor units. Orderly recruitment of the vagus nerve was produced in three dogs with a circuit superimposing 600-Hz, 3800-0-microA blocking over 10-70-Hz, 0-2300-microA stimulating currents. Amplitudes of motor unit or compound muscle action potentials were recorded from the thyroarytenoideus and cricopharyngeus via surface electromyographic electrodes. Stimulation was accompanied by a drop in UES intraluminal pressure. The reciprocal relationship between the two muscles could be time locked within certain stimulus parameters. We submit that electronic coupling between the glottic and UESs may show promise in preventing aspiration under selected circumstances.

Rheumatoid pannus of the cervical spine: a case report of an unusual cause of dysphagia.

Dysphagia as an initial complaint in rheumatoid arthritis is rare. We describe the case of a 69-year-old woman with rheumatoid arthritis who presented with a 2-day history of acute dysphagia. Our evaluation revealed the cause of the dysphagia was the presence of rheumatoid pannus that involved the anterior cervical spine and compressed the esophagus. Although the otolaryngologic manifestations of rheumatoid arthritis usually relate to synovial involvement of the temporomandibular and cricoarytenoid joints, our case establishes that a rheumatoid pannus on the anterior cervical spine can cause dysphagia. We believe that this may be the first reported case of this clinical entity.

Snoring, obstructive sleep apnea, and surgery.

Snoring and OSA syndrome are prevalent and important causes of sleep disturbance. Snoring, historically considered to be only a habitual annoyance, has significant physical and social consequences. OSA is now considered to be a major public health concern with significant morbidity and mortality. CPAP is considered the treatment of choice for OSA syndrome, but poor patient acceptance and compliance remain problematic. Surgical procedures have been developed to alter the offending anatomic abnormalities responsible for OSA. Identification of the offending anatomic site with application of the most appropriate surgical procedure is essential for effective surgical treatment of OSA. When the region of the retropalate is correctly identified as the site of obstruction, UPPP can effectively treat OSA in a majority of patients. Surgical correction of nasal obstruction is advocated in conjunction with sleep apnea surgery when nasal obstruction exists. In OSA patients with retrolingual airway obstruction, a number of surgical procedures have been performed, with or without UPPP, with some improvement over UPPP alone. MMO has been effective in the treatment of OSA in patients with significant retrolingual airway obstruction with contributing skeletal abnormalities and in patients who have failed multiple other surgical procedures. MMO, however, is a procedure of considerable magnitude, requiring extensive oromaxillofacial surgical expertise. MMO is likely appropriate only in a limited number of patients. Tracheostomy is completely effective in the treatment of OSA syndrome but is undesirable to patients and is associated with significant physical and emotional morbidity. Nonetheless, tracheostomy can be lifesaving and remains an option for patients with severe OSA with serious associated cardiovascular complications, who cannot tolerate CPAP, and for whom other interventions are ineffective or unacceptable. Effective surgical treatment of snoring has been accomplished with UPPP and LAUP. LAUP is less invasive, less morbid, more cost-effective, and better tolerated and is likely the most appropriate procedure for debilitating symptomatic snoring. Currently, LAUP is not recommended for the treatment of OSA, despite some efficacy in patients with mild OSA. Exclusion of OSA in patients undergoing LAUP for snoring is important.

Aggressive concurrent chemoradiotherapy for squamous cell head and neck cancer: an 8-year single-institution experience.

BACKGROUND: Since 1989, 105 patients with squamous head and neck cancer have been treated with combined chemoradiotherapy. OBJECTIVE: To examine the effectiveness of using combined chemoradiotherapy on patients with squamous head and neck cancer. DESIGN: Eight-year (1989-1997) single-institution evaluation of 105 patients. METHODS: Treatment consisted of fluorouracil, 1000 mg/m2 per day, and cisplatin, 20 mg/m2 per day, both given as continuous infusions during 4 days beginning on day 1 and 22 of a concurrent radiotherapy course. Radiation was given in single daily fractions of 1.8 to 2 Gy, to a total dose of 66 to 72 Gy. Salvage surgery was performed for any residual or recurrent locoregional disease. Planned neck dissection was recommended for all patients with N2+ neck disease, irrespective of clinical response. RESULTS: The 105-patient cohort consisted of 79 men and 26 women. The primary site was identified in the oral cavity in 6, oropharynx in 46, larynx in 30, and hypopharynx in 20 patients. Two patients had multiple primaries and 1 patient had an unknown primary. There were 4 patients with stage II, 24 with stage III, and 77 with stage IV disease. Grade 3 and 4 chemoradiotherapy toxic effects included mucositis in 88% of patients, cutaneous reaction in 50%, neutropenia in 49%, thrombocytopenia in 12%, and nausea in 5%. There were no deaths secondary to treatment. The mean weight loss was 12% of initial body weight. To date, primary site persistence or recurrence has occurred in only 14 patients (13%). With a mean follow-up of 39 months, 66 patients (63%) are alive and free of disease. The Kaplan-Meier 4-year projected overall survival is 60% with a disease-specific survival of 74%, a distant metastasis-free survival of 84%, and an overall survival with primary site preserved of 54%. CONCLUSIONS: This chemoradiotherapy regimen, although toxic, is tolerable with appropriate supportive intervention. Locoregional and distant control are likely. Primary site conservation is possible in most patients. Chemoradiotherapy appears to have an emerging role in the primary management of head and neck cancer.

Dysphagia in patients with inclusion body myositis.

OBJECTIVES: Inclusion body myositis (IBM) is an inflammatory myopathy with a 40% reported incidence of dysphagia. A protracted course, refractory to medical therapy, frequently leads to consultation with an otolaryngologist for dysphagia management. We studied the incidence, symptoms, and mechanisms of dysphagia in patients with IBM. STUDY DESIGN: Retrospective study of medical records and self-reported follow-up survey; dysphagia is defined as difficulty in swallowing. MATERIALS: Twenty-two patients with biopsy-proven IBM. RESULTS: The rate of dysphagia was more than 80% (16 of 19), twice as high as previously reported. Progressive dysphagia was associated with a significantly worse functional class. Relevant management guidelines are established, including the timing for appropriate surgical intervention. CONCLUSION: Progressive dysphagia may signify more aggressive IBM or an episodic worsening in status. Recognition of the disease manifestations will afford proper patient management. Informed otolaryngologists can have a favorable impact on the dysphagia associated with IBM.

Long-term excitability and fine tuning of nerve pedicles reinnervating strap muscles in the dog.

Contraction of paralyzed striated muscles has been restored by stimulating reinnervating pedicles with currents of low intensity. In order to allow clinical application, stable, long-term excitability must emulate the parameters necessary for the stimulation of normal motor nerves. In 6 dogs, the ansa hypoglossi nerve was implanted into the contralateral denervated sternohyoid muscle and surrounded with a bipolar cuff electrode. Three of the reinnervating pedicles were chronically paced with a Medtronic Itrel II Multiprogrammable Pulse Generator (0.5 V, 0.2 second on [30 pulses per second, 0.21-millisecond pulse width], 2.9 seconds off). At reexploration after 8 months (6 months for 1 dog), frank contraction confirmed by electromyography tracings occurred in all animals with currents in the range of 0.1 to 0.5 mA. Muscle force was further manipulated by selective release of blocking currents (600 Hz, 1.7 to 0.4 mA) superimposed over regular stimulation (50 Hz, 0.3 to 1.7 mA). Nerve and muscle vitality were histologically confirmed. Long-term, low-intensity conduction capabilities, fine tuning, good tolerance of implanted electrodes, and lack of fatigue suggest that reinnervating pedicles may be successfully used for pacing when clinically indicated.