Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.

BACKGROUND: Hypoglossal nerve stimulation has been demonstrated to relieve upper airway obstruction acutely, but its effect on obstructive sleep apnea is not known. OBJECTIVE: To determine the response in obstructive sleep apnea to electrical stimulation of the hypoglossal nerve. METHODS: Eight patients with obstructive sleep apnea were implanted with a device that stimulated the hypoglossal nerve unilaterally during inspiration. Sleep and breathing patterns were examined at baseline before implantation and after implantation at 1, 3, and 6 months and last follow-up. RESULTS: Unilateral hypoglossal nerve stimulation decreased the severity of obstructive sleep apnea throughout the entire study period. Specifically, stimulation significantly reduced the mean apnea-hypopnea indices in non-rapid eye movement (mean +/- SD episodes per hour, 52.0 +/- 20.4 for baseline nights and 22.6 +/- 12.1 for stimulation nights; P<.001) and rapid eye movement (48.2 +/- 30.5 and 16.6 +/- 17.1, respectively; P<.001) sleep and reduced the severity of oxyhemoglobin desaturations. With improvement in sleep apnea, a trend toward deeper stages of non-rapid eye movement sleep was observed. Moreover, all patients tolerated long-term stimulation at night and did not experience any adverse effects from stimulation. Even after completing the study protocol, the 3 patients who remained free from stimulator malfunction continued to use this device as primary treatment. CONCLUSION: The findings demonstrate the feasibility and therapeutic potential for hypoglossal nerve stimulation in obstructive sleep apnea.

Long-term monitoring of respiration with a mediastinal pressure sensor in dogs.

The ability of an implanted mediastinal pressure sensor to produce a stable respiratory signal that could be used to trigger stimulation of upper airway muscles was examined. In 6 dogs, a pressure sensor was secured to the manubrium (4 by wires and 2 by transmanubrial placement). In 6 other dogs, the pressure sensor was placed in the upper anterior mediastinum. The animals were monitored for a minimum of 8 weeks (2 transmanubrial sensors for 12 months). Sensors that were able to maintain a midline position, high in the mediastinum, had the best signals. A caudal sensor position or abutment against an intrathoracic structure caused signal inversion (unusable signals). Transmanubrial placement resulted in a stable signal for 1 year. We conclude that long-term monitoring of respiration with a mediastinal pressure sensor can be successfully performed in dogs, providing an adequate signal for nerve-muscle stimulation. Separation from cardiovascular structures improves signal quality.

Effects of intralaryngeal carbon dioxide and acetazolamide on the laryngeal chemoreflex.

Sudden infant death syndrome is the leading cause of death in infants in the United States. The laryngeal chemoreflex (LCR) is thought to contribute to its pathogenesis. In adult animals, increasing levels of intralaryngeal CO2 result in a decrease in ventilatory activity. Intravenous acetazolamide (AZ) abolishes this response. The purpose of this study was to determine the effects of intralaryngeal CO2 and AZ on the LCR and respiratory physiology of piglets under normoxic and hypoxic conditions. We applied 0% or 10% CO2 in a randomized order to the larynx of 26 piglets. Intubation via tracheotomy prevented inhalation of the gas mixtures. Laryngeal stimulation was performed under normoxic conditions (PaO2 of >70 mm Hg) in 15 animals and under hypoxic conditions (PaO2 of 50 to 65 mm Hg) in 11 animals both with and without intravenous AZ (5 mg/kg). Respiratory and cardiovascular response data were recorded. Ten percent intralaryngeal CO2 has no significant effect on mean baseline respiratory rate, systemic PaCO2 or PaO2 levels, or apnea duration (p > .05). The use of AZ (versus no AZ) resulted in significantly higher baseline respiratory rates (64 versus 51 breaths per minute; p = .016), a decreased baseline systemic PaCO2 level (38.8 versus 45.9 mm Hg; p < .001), a higher baseline PaO2 level (97.9 versus 82.8 mm Hg; p < .001), shorter mean apnea durations (15.5 versus 24.8 seconds; p = .001), a higher lowest O2 saturation level after the stimulus (78.0% versus 68.4%; p = .003), and fewer profound apneas (10 of 90 versus 41 of 90 trials; p < .001). We conclude that 10% intralaryngeal CO2 does not decrease ventilatory activity in piglets and has no significant effect on the LCR. Acetazolamide, however, appears to have a protective effect against the LCR, resulting in shorter and less severe apneas. The protective effect of AZ against the LCR appears to be related to its ability to stimulate the respiratory drive and increase oxygenation at baseline.

Second place-resident clinical science award 1999: laryngeal chemoreflex severity and end-apnea PaO(2) and PaCO(2).

OBJECTIVE: The laryngeal chemoreflex (LCR) is a model for investigating the sudden infant death syndrome. The severity of the LCR-induced response may vary. This study examines the conditions under which recovery from the LCR-induced apnea occurs. METHODS: Twenty-five piglets underwent normoxic laryngeal stimulation (Pao(2) > 70 mm Hg); 11 then underwent hypoxic stimulation (Pao(2) 50-65 mm Hg). Cardiovascular and respiratory responses were recorded. RESULTS: Recovery Pao(2) was lower during profound responses (Pao(2) = 45.9 +/- 12.8 mm Hg) than during moderate (Pao(2) = 54.9 +/- 7.5 mm Hg) and mild (Pao(2) = 60.6 +/- 10.3 mm Hg) responses (analysis of variance [ANOVA], P = 0.05). Recovery PaCO(2) did not vary (ANOVA, P > 0.05). Blood pressure and O(2) saturation declined at faster rates with increasing severity of response (ANOVA, P < 0.05 for both). CONCLUSIONS: Resumption of respiration after LCR-induced apnea is associated with a consistent level of PaCO(2). The severity of the response is associated with recovery PaO(2) levels.

The effects of conjugated deferoxamine in porcine skin flaps.

BACKGROUND: The free radical scavenger, deferoxamine (DFO) has been shown to reduce skin flap necrosis; however, its shortcomings are its toxicity and short plasma half-life. METHODS: This study investigates the effects of the less toxic, longer acting conjugated form, DFO-Hespan (DFO-H), to ischemic porcine skin flaps. During the study, DFO-H plasma concentrations and flap viability were evaluated over 10 days. RESULTS: Steady DFO serum levels were maintained with no evidence of systemic side effects. However, DFO-H was not effective in increasing porcine skin flap viability. Mean treated flap viability (n = 18) was 36.2% +/- 1.7% (mean +/- SE ) vs control (n = 16) 35.8% +/- 2.6%, p =.9. CONCLUSION: DFO-H conjugation increases its half-life and its systemic tolerance for DFO. However, this conjugation may also reduce DFO's effectiveness to preserve flap survival probably by decreasing its ability to reach the intracellular oxygen free radicals. In addition, further studies are needed to investigate whether longer DFO administration given postoperatively can be more effective in reducing ischemic injury.

Doxorubicin chemomyectomy: effects on evoked vocal fold tension and mucosal wave.

Chemomyectomy of the thyroarytenoid muscle is a potential alternative approach to the management of spasmodic dysphonia (laryngeal dystonia) that could provide a prolonged response. To be useful, chemomyectomy should produce weakening of vocal fold closure without disruption of the mucosal wave. Sixteen dogs were studied. In 8 animals, doxorubicin hydrochloride (3 mg) and verapamil hydrochloride (0.5 mg) were injected unilaterally into the thyroarytenoid muscle 2 months before evaluation. The remaining animals served as noninjected controls. Injection of doxorubicin and verapamil decreased the average evoked tension of the vocal fold by 74.7%, compared to an average side-to-side difference of 12.7% in the control group (p = .001). A mucosal wave was recognized bilaterally with videostroboscopy in all dogs. Doxorubicin did not significantly change the vocal fold appearance or mucosal wave amplitude. These results support further laboratory study of chemomyectomy as a potential alternative treatment for laryngeal dystonia.

A new role for magnetic resonance imaging in the diagnosis of laryngeal relapsing polychondritis.

BACKGROUND: Relapsing polychondritis involving the upper airway is a rare cause of airflow obstruction and hoarseness. The diagnosis of relapsing polychondritis depends on clinical signs, characteristic findings on cartilage biopsy, and response to treatment. Delays in diagnosis and treatment can increase the morbidity and mortality of the disease. METHODS: We present a case report of primary laryngeal relapsing polychondritis. RESULTS: Serologic testing, direct laryngoscopy, and endoscopic biopsy could not establish the diagnosis of relapsing polychondritis. Magnetic resonance imaging (MRI) examination demonstrated findings consistent with the histopathological diagnosis obtained on open biopsy. Follow-up MRI after treatment showed resolution of the initial findings. CONCLUSION: This case demonstrates the usefulness of MRI in the diagnosis and management of relapsing polychondritis involving the upper airway.

Relationship of the posterior cricoarytenoid muscle to the posterior cricoid lamina.

OBJECTIVE: Early experiments in functional electrical stimulation of the posterior cricoarytenoid muscle (PCA) in human beings have involved placement of the electrode along the undersurface of the PCA. The anatomy of the posterior cricoid lamina (PCL) was examined to obtain a quantitative understanding of this region. METHODS: Thirty fresh-frozen cadaver larynges were dissected. Measurements of the cricoid cartilage and PCA were obtained with a caliper or calibrated probe. RESULTS: Twenty male and 10 female adult larynges were examined. Sex differences were found for the height of the PCL. All larynges had approximately 4 mm of exposed cartilage along the inferior surface of the PCL. The origin of the PCA on the PCL was thinner in the medial-vertical attachment than in the inferior-horizontal. The average inferolateral to superomedial diagonal width of the PCA was 4 mm greater in the male than in the female larynges. Asymmetry between the left and right sides was seen. CONCLUSIONS: The PCA can be divided into 2 muscle groups based on its origin on the PCL as well as its insertion into the muscular process of the arytenoid. The quantitative information obtained has implications for electrode design and placement for laryngeal stimulation.

Effect of sleep state on the laryngeal chemoreflex in neonatal piglets.

The laryngeal chemoreflex (LCR) is a brain stem-mediated response that is a potential mechanism for sudden infant death syndrome. The vast majority of sudden infant death occurs during sleep, yet it remains to be established whether there is a particular sleep state that makes an infant animal more susceptible to apneic events via the LCR. The purpose of this study was to investigate the LCR during different sleep states in the neonatal piglet. In this study, continuous physiologic monitoring and electroencephalographic, electro-oculographic, and electromyographic techniques were utilized to study neonatal piglets during a hypnotic induced sleep model. Propofol drip anesthetic was utilized to provide an anesthetic state and was titrated for dose-dependent sedation. The LCR was initiated in 11 animals during quiet sleep, rapid eye movement sleep, and the anesthetic state. Baseline respiratory and cardiovascular responses were measured. Durations of apnea were recorded and compared. This study found that despite known physiologic differences in respiratory control during different sleep states as compared to the anesthetic state, there appears to be no increased risk of profound apnea in one state versus another in piglets 19 to 28 days old.

Acoustic and perceptual evaluation of laryngeal reinnervation by ansa cervicalis transfer.

OBJECTIVES/HYPOTHESIS: To evaluate the acoustic and perceptual results of laryngeal reinnervation with ansa cervicalis to recurrent laryngeal nerve anastomosis. STUDY DESIGN: Retrospective study of voice samples from 12 patients with unilateral recurrent laryngeal nerve paralysis, treated with ansa cervicalis to recurrent laryngeal nerve anastomosis. Samples were recorded before surgery and at least 8 months after surgery. METHODS: The samples were subjected to several acoustic analyses sensitive to paralytic dysphonia, including cepstral peak prominence, noise-to-harmonics ratio, and measures of frequency and amplitude perturbation. The voice samples from the patients were randomized with age- and sex-matched samples from normal subjects and judged by trained listeners for overall dysphonia, roughness, breathiness, asthenia, and strain. The preoperative and postoperative results were compared statistically, and the postoperative results were compared with the matched normal subjects. RESULTS: As a group, the patients showed improvement (P < .05) in cepstral peak prominence, frequency perturbation, and perceptual judgments of overall dysphonia, breathiness, and asthenia. The best results occurred in patients with isolated vocal fold paralysis. The postoperative group as a whole did not improve to the level seen in matched normals. Suboptimal results were seen primarily in patients with untreated laryngeal or extralaryngeal pathology beyond the laryngeal paralysis. CONCLUSIONS: These data suggest that laryngeal reinnervation has the potential to bring about a return to normal or near-normal voice in patients with isolated unilateral vocal fold paralysis.

Correlation of laryngeal chemoreflex severity with laryngeal muscle response.

OBJECTIVES: To examine the relationship between the severity of the laryngeal chemoreflex (LCR) and the pattern of laryngeal muscle activity during an LCR-induced apnea. METHODS: The laryngeal mucosa of 20 piglets aged 17 to 20 days was stimulated under both hypoxic and normoxic conditions. Respiration, blood pressure, and activity of the thyroarytenoid (TA) and posterior cricoarytenoid (PCA) muscles were monitored during the LCR-induced apnea. RESULTS: Hypoxemia resulted in a shorter average apnea duration but a greater degree of hypotension. All piglets recovered spontaneously following normoxic LCR stimulation. Hypoxic stimulation resulted in two divergent apneic responses: transient with a spontaneous recovery (17 piglets) or profound requiring resuscitation (three piglets). An increase in TA muscle activity and a decrease in PCA muscle activity was the most common response to LCR stimulation. The response of the TA and PCA muscles was maintained in piglets destined for spontaneous recovery. Decreasing TA activity and increasing PCA activity correlated with the development of a profound response. CONCLUSIONS: The piglet demonstrates two distinct responses to hypoxic laryngeal chemostimulation that correlate with the activity of the intrinsic laryngeal muscles. Failure to maintain the activity of the TA and PCA muscles during a profound response is associated with the development of severe cardiovascular instability. This study suggests that the critical event involving the LCR is the development of complications secondary to hypoxia.

Relief of upper airway obstruction with hypoglossal nerve stimulation in the canine.

Hypoglossal nerve stimulation was investigated as a method to relieve an induced upper airway obstruction. Six dogs were implanted with a cuff electrode applied to each hypoglossal nerve and a pulse generator. After 4 weeks, the hypoglossal nerve was stimulated (50% duty cycle) for up to 8 weeks. At 12 weeks a double tracheotomy was placed, with a negative pressure intermittently applied to the upper limb, simulating inspiratory airway pressure. Unilateral hypoglossal nerve stimulation improved peak upper airway flow from an average of 0.1 L/s to 1.6 L/s (P = 0.0001). Seventy-seven percent of the maximum possible flow (explanted tracheotomy tube) was obtained with unilateral stimulation. Histopathological evaluation revealed no nerve damage secondary to chronic stimulation. This study provides support for clinical trials of hypoglossal stimulation for obstructive sleep apnea.

Effect of antagonism at central nervous system M3 muscarinic receptors on laryngeal chemoresponse.

The laryngeal chemoresponse (LCR), comprising laryngeal adductor spasm, central apnea, and subsequent cardiovascular instability, is thought to be a factor in sudden infant death syndrome. A muscarinic subtype receptor, M3, appears to be involved in central respiratory drive and control. Both the duration of the LCR apnea and levels of M3 receptor messenger RNA in the brain stem change according to postnatal age. This study examined the effect of central nervous system antagonism at M3 receptors on the LCR with respect to animal age and dose of antagonist. Ten piglets in each of three age groups (group 1, 5 to 8 days; group 2, 18 to 21 days; and group 3, 40 to 43 days) received a series of four increasing doses of an M3 antagonist (p-fluoro-hexahydro-sila-diphenidol) by intracerebral ventricle injection. The LCR was evoked at baseline and after each dose of antagonist. An effect on susceptible animals (groups 1 and 2) was evident by the second antagonist dose, and persisted for the remainder of the experiment (2 hours). At completion of the experiment, mean apnea duration had decreased in group 1 (61%, p < .05), and group 2 (57%, p < .05), but was unchanged in group 3 (<10%, p not significant). Length of mean baseline apneas correlated directly with degree of apnea shortening. The reduction is not attributable to changes in arterial PO2 or PCO2 or baseline respiratory rate. These results support an age-related influence on the LCR by M3 receptors in younger animals that decreases with maturation.

Spasmodic dysphonia symptoms as initial presentation of amyotrophic lateral sclerosis.

A patient initially diagnosed with adductor-type spasmodic dysphonia was referred for botulinum toxin (Botox) injections, but found on subsequent evaluation to have amyotrophic lateral sclerosis, and therefore Botox was not administered. This unique case underscores the need to delay botulinum toxin treatments in any patient with recent onset symptoms, and to obtain thorough motor speech and voice, otolaryngologic, and neurologic evaluation in all patients prior to consideration for injection.

Effect of topical diphenhydramine on the laryngeal chemoreflex.

OBJECTIVE: To study diphenhydramine nebulization as a clinically applicable method for blunting laryngeal chemoreflex (LCR)-associated apnea. INTERVENTIONS: Fourteen piglets aged 15 to 18 days were studied. In 7 piglets, diphenhydramine hydrochloride (5.0 mg/kg) was nebulized onto the laryngeal mucosa after a baseline response was obtained. RESULTS: After a 10-minute waiting period, the mean +/- SD LCR-induced apnea duration decreased from 29 +/- 13 seconds in the control animals to 15 +/- 5 seconds in the treated group (P = .02, 1-factor analysis of variance). After 1 hour, no treatment effect was seen. CONCLUSIONS: Nebulization of diphenhydramine can effectively reduce LCR-induced apnea for a short time. Nebulization of longer-acting agents may provide an effective prophylaxis of LCR-induced apnea.

Effect of a second laryngeal stimulation during recovery from the laryngeal chemoreflex.

The laryngeal chemoreflex is a potential mechanism for sudden infant death. In experimental protocols in which a full recovery is allowed between stimuli, no laryngeal chemoreflex responses result in a fatal outcome. In the clinical situation there are no controls to prevent repeated laryngeal stimulation before a full recovery. The effect of a laryngeal stimulus applied during or soon after a laryngeal chemoreflex-induced apnea was investigated. Eighteen piglets were divided into groups aged 10 to 12 days, 17 to 21 days, and 32 to 36 days. Laryngeal stimulation was performed under normoxic conditions with water applied to the mucosa. Baseline respiratory and cardiovascular response data were measured. After recovery an initial stimulation was applied, followed by a second stimulation during the apnea or 5, 30, 60, or 120 seconds after restoration of breathing. No profound apneas occurred with baseline laryngeal stimulation. In piglets aged 32 to 36 and 17 to 21 days, a second laryngeal stimulus resulted in a shortened apnea duration. The response varied in piglets aged 10 to 12 days with profound apneas observed in 2 of 6 subjects and 4 of 30 trials. Piglets aged 17 to 36 days are less susceptible to the laryngeal chemoreflex during the immediate recovery period. In piglets aged 10 to 12 days, the laryngeal chemoreflex response may be more severe after a second stimulus.

The effect of antihistamines on the laryngeal chemoreflex.

The laryngeal chemoreflex (LCR) consists of apnea, laryngospasm, and cardiovascular changes in neonates after laryngeal irritation and has been implicated in sudden infant death syndrome and apnea of infancy. Antihistamines attenuate a similar vagally mediated pulmonary chemoreflex. The intravenous antihistamine effect on the LCR was studied in neonatal piglets. Laryngeal muscle activity, respiration, blood pressure, and pulse were measured during water stimulation of the LCR. After baseline LCR recordings, intravenous diphenhydramine (2.5 mg/kg) or cimetidine (20 mg/kg) was bolused (control group received saline). LCR measurements were repeated over 7 hours. Diphenhydramine significantly shorted apneas (P < .05) 3 to 7 hours after drug bolus, which is believed to be secondary to central atropinic effects. Cimetidine demonstrated no attenuation of the LCR.

Postoperative respiratory compromise in children with obstructive sleep apnea syndrome: can it be anticipated?

OBJECTIVE: The aim of this research was to describe the postoperative respiratory complications after tonsillectomy and/or adenoidectomy (T and/or A) in children with obstructive sleep apnea syndrome (OSAS), to define which children are at risk for these complications, and to determine whether continuous positive airway pressure (CPAP) is an effective strategy for dealing with these complications. METHODS: The data for this study were gathered through a retrospective chart review of all children 15 years of age or younger with polysomnographically (PSG) proven OSAS who had a T and/or A at Hennepin County Medical Center between January 1985 and September 1992. Particular attention was paid to factors that contributed to the OSAS, postoperative respiratory complications, and intervention strategies for dealing with these complications. RESULTS: The charts of 37 children with OSAS documented by preoperative PSG who later had a T and/or A were reviewed retrospectively. Ten of these children had significant postoperative respiratory compromise secondary to OSAS that prolonged their hospital stay from 1 to 30 days and caused symptoms ranging from O2 desaturation < 80% to respiratory failure. These children were younger and had significant associated medical problems that contributed to or resulted from their OSAS in addition to large tonsils and adenoids. The associated medical problems included craniofacial anomalies, hypotonia, morbid obesity, previous upper airway trauma, cor pulmonale, and failure to thrive. The children with postoperative respiratory complications also had more severe apnea on their preoperative PSG. One child had a uvulopalatopharyngoplasty (UPPP) in addition to the T & A. Taken together, the history, physical and neurological examination, and the PSG were able to identify successfully the children who subsequently developed respiratory compromise secondary to OSAS after a T and/or A. Nasal continuous positive airway pressure (CPAP) and bilevel CPAP was used successfully to manage the preoperative and/or postoperative upper airway obstruction in five of these children. CONCLUSIONS: Based on these findings, overnight observation is recommended with an apnea monitor and oximeter for patients undergoing a T and/or A who have OSAS and meet any of the following high-risk clinical criteria: (1) < 2 years of age, (2) craniofacial anomalies affecting the pharyngeal airway particularly midfacial hypoplasia or micro/retrognathia, (3) failure to thrive, (4) hypotonia, (5) cor pulmonale, (6) morbid obesity, and (7) previous upper airway trauma; or high-risk PSG criteria: (1) respiratory distress index (RDI) > 40 and (2) SaO2 nadir < 70%; or undergoing a UPPP in addition to the T and/or A. Nasal CPAP/bilevel CPAP can be used to manage the preoperative and/or postoperative upper airway obstruction in patients with OSAS undergoing a T and/or A.

The effects of the inhalational anesthetic agent combination, isoflurane-nitrous oxide, on survival in a pig random skin flap model.

Using a dorsally based, random skin flap model in 14 swine, the influence on skin flap survival of isoflurane used with nitrous oxide as maintenance anesthetic agents was examined. The mean area of skin flap survival was 54.9% for the experimental group compared with 28.6% in the control group. Arterial blood gas content (PO2, PCO2, and HCO3-), respiratory rate, acid-base balance, blood pressure level, pulse rate, and temperature were monitored. Improved survival of the isoflurane-nitrous oxide group was independent of these parameters. These data support the findings of a previous study that isoflurane positively affects random skin flap survival in a swine model. Furthermore, the addition of nitrous oxide partially reduces isoflurane's beneficial effects.

Rehabilitation of the lower cranial nerves.

Brain stem lesions frequently cause dysfunction of the lower cranial nerves. Even with successful treatment, dysfunction may remain. Various methods for rehabilitating the patient with persistent lower cranial nerve dysfunction are presented.