Electrical stimulation of the whole hypoglossal nerve in patients with obstructive sleep apnea.

PURPOSE: Electrical stimulation of the whole hypoglossal nerve (HGp-ES) has been demonstrated to enlarge the pharynx and improve pharyngeal stability and patency to airflow in all animals studied, but not in humans. The present study was undertaken to better understand the effect of HGp-ES on the human pharynx. METHODS: Eight patients with obstructive sleep apnea who had implanted stimulators with electrodes positioned proximally on the main truck of the hypoglossus were studied under propofol sedation. Pharyngoscopy and air flow measurements at multiple levels of continuous positive airway pressure (CPAP) were performed before and during Hgp-ES. RESULTS: HGp-ES that activates both tongue protrusors and retractors narrowed the pharyngeal lumen at the site of collapse (velopharynx in all subjects) from 1.38 ± 0.79 to 0.75 ± 0.44 cm2, p < 0.05 (measured at mid-range of CPAP levels) and lowered airflow (from 8.88 ± 2.08 to 6.69 ± 3.51 l/min, p < 0.05). Changes in critical pressure (Pcrit) and velopharyngeal compliance were not significant, but oropharyngeal compliance decreased (from 0.43 ± 0.18 to 0.32 ± 0.13 cm2/cmH2O, p < 0.05). No correlation was found between the pattern of change in luminal shape (determined as the ratio of a-p vs. lateral diameter when lowering CPAP) or changes in cross-sectional area and airflow during Hgp-ES. CONCLUSIONS: Our findings indicate that human retractors dominate when stimulated together with the protrusors during HGp-ES. While co-activation of retractors may be beneficial, it should be limited. We speculate that exercises that augment protrusor force may improve the response to hypoglossal stimulation. The exclusion of patients with concentric pharyngeal obstruction should be re-evaluated.

Parameters affecting pharyngeal response to genioglossus stimulation in sleep apnoea.

Chronic stimulation of the hypoglossus nerve may provide a new treatment modality for obstructive sleep apnoea (OSA). In previous studies we observed large differences in response to stimulation of the genioglossus (GG). We hypothesised that both individual patient characteristics and the area of the GG stimulated are responsible for these differences. In the present study, we compared the response to GG electrical stimulation at the anterior area (GGa-ES), which activates the whole GG and the posterior area (GGp-ES), which activates preferentially the longitudinal fibres. Studies were performed in 14 propofol-sedated OSA patients. The parameters evaluated included cephalometry, pressure-flow relationship and pharyngeal shape and compliance assessed by pharyngoscopy. Compared with GGa-ES, GGp-ES resulted in significantly larger decreases in the critical value of end-expiratory pressure (P(crit)) (from 3.8 ± 2.2 to 2.9 ± 3.3 and -2.0 ± 3.9 cmH(2)O, respectively (p<0.001)). Both tongue size and velopharyngeal shape (anteroposterior to lateral ratio) correlated significantly with the decrease in P(crit) during GGp-ES (R = 0.53 and -0.66, respectively; p<0.05). In the patients with the larger tongue size (n = 7), the decrease in P(crit) reached 8.0 ± 2.2 cmH(2)O during GGp-ES. We conclude that directing stimulation to longitudinal fibres of the GG improves the flow-mechanical effect. In addition, patients with large tongues and narrow pharynx tend to respond better to GGp-ES.

Implementation of a web-based interactive virtual patient case simulation as a training and assessment tool for medical students.

OBJECTIVE: Structured Clinical Examinations (OSCE) are resource intensive, not practical as teaching tools, and their reliability depends on evaluators. Computer-based case simulations ("virtual patients", VP) have been advocated as useful and reliable tools for teaching clinical skills and evaluating competence. We have developed an internet-based VP system designed both for practice and assessment of medical students. The system uses interactive dialogue with natural language processing, and is designed for history taking, evaluation of physical examination, including recognition of visual findings and heart and lung sounds, and ordering lab-and imaging tests. The system includes a practice modality that provides feedback, and a computerized OSCE. The reliability of our system was assessed over the last three years by comparing the clinical competence of medical students in similar VP and human OSCE. A total of 262 students were evaluated with both exam modalities. The correlation between the two exams scores was highly significant (p<0.001). Alpha Cronbach for the computerized exam was 0.82-0.89 in the 3 years, and was substantially higher than that of the conventional OSCE each year. We conclude that a computerized VP OSCE is a reliable examination tool, with the advantage of providing also a training modality.

Collapsibility of the relaxed pharynx and risk of sleep apnoea.

The present study measured hypotonic pharyngeal collapsibility in subjects not known to have obstructive sleep apnoea (OSA), and assessed the variables that affect collapsibility and the relationship with OSA. The critical value of positive end-expiratory pressure (P(crit)) was measured under the hypotonic condition of anaesthesia in 227 subjects who underwent elective surgery. The risk of OSA in this population was estimated using the Berlin questionnaire. The mean P(crit) for all subjects was positive (above atmospheric), ranging from 0.69 (95% confidence interval (CI) -7.39-8.77) to 4.0 (CI -4.82-12.82) cmH(2)O for subjects with low and high prevalence of OSA, respectively. P(crit) < or = -5 cmH(2)O was only found in 3.1% of the study subjects. In the general population, P(crit) was similar in males and females and correlated positively with increasing age, while a correlation with neck circumference was found only in males. P(crit )accounted for only 12.25% of the variability in OSA risk score. In conclusion, subjects with high critical value of positive end-expiratory pressure are at an increased risk for developing obstructive sleep apnoea. However, the human pharynx is prone to collapse and occludes in most people in the absence of neuromuscular support. Therefore, in most subjects, the level of neuromuscular activity may ultimately determine the occurrence of sleep apnoea.

Mechanisms underlying CO2 retention during flow-resistive loading in patients with chronic obstructive pulmonary disease.

The present study examined the respiratory responses involved in the maintenance of eucapnea during acute airway obstruction in 12 patients with chronic obstructive disease (COPD) and 3 age-matched normal subjects. Acute airway obstruction was produced by application of external flow-resistive loads (2.5 to 30 cm H2O/liter per s) throughout inspiration and expiration while subjects breathed 100% O2. Application of loads of increasing severity caused progressive increases in PCO2 in the patients, but the magnitude of the increase in PCO2 varied substantially between subjects. On a resistance of 10 cm H2O/liter per s, the highest load that could be tolerated by all COPD patients, the increase in PCO2 ranged from 1 to 11 mm Hg, while none of the normal subjects retained CO2. Based on the magnitude of the increase in PCO2 the patients could be divided into two groups: seven subjects whose PCO2 increased by less than or equal to 3 mm Hg (group I) and five subjects whose PCO2 increased by greater than 6 mm Hg (group II). Base-line ventilation and the pattern of breathing were similar in the two groups. During loading group I subjects maintained or increased tidal volume while all group II patients decreased tidal volume (VT). The smaller tidal volume in group II subjects was mainly the result of their shorter inspiratory time as the changes in mean inspiratory flow were similar in the two groups. The magnitude of CO2 retention during loading was inversely related to the magnitude of the change in VT (r = -0.91) and inspiratory time (Ti) (r = -0.87) but only weakly related to the change in ventilation (r = -0.53). The changes in PCO2, VT, and Ti during loading correlated with the subjects' maximum static inspiratory pressure, which was significantly lower in group II as compared with group I patients. These results indicate that the tidal volume and respiratory timing responses to flow loads are impaired in some patients with COPD. This impairment, presumably due to poor inspiratory muscle function, appears to lead to CO2 retention during loaded breathing.

Effect of positional changes of anatomic structures on upper airway dilating muscle shortening during electro- and chemostimulation.

Positional changes of anatomic structures surrounding the upper airway are known to affect pharyngeal mechanics and collapsibility. We hypothesized that these alterations also affect the ability of the upper airway dilator muscles to enlarge the pharynx by altering their ability to shorten when activated. Using sonomicrometry, we evaluated in seven anesthetized dogs the effects of changes in tracheal and head position on the length of the genioglossus (GG) and the geniohyoid (GH) and the effects of these positional changes on the magnitude of shortening of the two muscles in response to electro- (ES) and chemostimulation (CS). Caudal traction of the trachea lengthened the GG and GH in all dogs, whereas cranial displacement of the trachea and flexion of the head to a vertical position shortened the muscles. Compared with the magnitude of ES-induced shortening in the neutral position, ES-induced shortening of the GG was 144.7 +/- 14.6, 49.3 +/- 4.3, and 33.5 +/- 11.6% during caudal and cranial displacement of the trachea and during head flexion, respectively. Similar effects of the positional changes were found for the GH, as well as for both muscles during respiratory stimulation with P(CO2) of 90 Torr at the end of CO(2) rebreathing, although inspiratory muscle shortening during CS reached only one-quarter to one-third of the magnitude observed during ES. We conclude that positional alterations of anatomic structures in the neck have a dramatic effect on the magnitude of shortening of the activated GG and GH, which may reduce substantially their ability to protect pharyngeal patency.

Differential effects of respiratory and electrical stimulation-induced dilator muscle contraction on mechanical properties of the pharynx in the pig.

Respiratory stimulation (RS) during sleep often fails to discontinue flow limitation, whereas electrical stimulation (ES) of the hypoglossus (HG) nerve frequently prevents obstruction. The present work compares the effects of RS and HG-ES on pharyngeal mechanics and the relative contribution of tongue muscles and thoracic forces to pharyngeal patency. We determined the pressure-area relationship of the collapsible segment of the pharynx in anesthetized pigs under the following three conditions: baseline (BL), RS induced by partial obstruction of the tracheostomy tube, and HG-ES. Parameters were obtained also after transection of the neck muscles and the trachea (NMT) and after additional bilateral HG transection (HGT). In addition, we measured the force produced by in situ isolated geniohyoid (GH) during RS and HG-ES. Intense RS was recognized by large negative intrathoracic pressures and triggered high phasic genioglossus and GH EMG activity. GH contraction produced during maximal RS less than a quarter of the force obtained during HG-ES. The major finding of the study was that RS and ES differed in the mechanism by which they stabilized the pharynx: RS lowered the pressure-area slope, i.e., reduced pharyngeal compliance (14.1 ± 2.9 to 9.2 ± 1.9 mm(2)/cmH2O, P < 0.01). HG-ES shifted the slope toward lower pressures, i.e., lowered the calculated extraluminal pressure (17.4 ± 5.8 to 9.2 ± 7.4 cmH2O, P < 0.01). Changes during RS and HG-ES were not affected by NMT, but the effect of RS decreased significantly after HGT. In conclusion, HG-ES and RS affect the pharyngeal site of collapse differently. Tongue muscle contraction contributes to pharyngeal stiffening during RS.

Correlation between levels of tumour necrosis factor-alpha and levels of pH, glucose, and lactate dehydrogenase in parapneumonic effusions.

OBJECTIVES: This study was undertaken to investigate the correlation, which has not been previously investigated, between levels of tumour necrosis factor-alpha (TNF) and levels of pH, glucose, and lactate dehydrogenase (LDH) in pleural fluid of patients with uncomplicated parapneumonic effusion (UCPPE), and patients with complicated parapneumonic effusion (CPPE). METHODS: Using a commercially-available high sensitivity ELISA kit, levels of TNF were measured in pleural fluid of patients with UCPPE (n = 23), and CPPE (n = 15), and were compared with levels of pH, glucose, and LDH in these two groups. RESULTS: The mean +/- SD values of pleural fluid TNF, pH, glucose, and LDH in the UCPPE group were 11.05 +/- 7.65 pg/ml, 7.41 +/- 0.08, 125 +/- 48 mg/dl, and 306 +/- 182 IU/l, respectively. In the CPPE group the values were 56.07 +/- 28.5 pg/ml, 6.82 +/- 0.25, 42 +/- 36 mg/dl, and 2096 +/- 1916 IU/l, respectively. The only significant correlation, which was negative, was found between levels of TNF and pH in the CPPE group (r = -0.62, P = 0.01). Levels of pleural fluid TNF and LDH were significantly higher, and levels of glucose were significantly lower in the CPPE group than in the UCPPE group (P < 0.0001). CONCLUSIONS: This study demonstrates, for the first time that TNF levels correlate inversely with levels of pH in pleural fluid of patients with CPPE but not of patients with UCPPE. This correlation may, in part, explain the pathophysiology of the pleural complications which occur in the presence of CPPE.

Hyponatremia during therapy with amiodarone.

We describe an elderly woman who presented with significant hyponatremia caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) during therapy with amiodarone. The hyponatremia resolved after discontinuation of the drug and did not recur during a follow-up period of 6 months. Such an association has previously been reported only once in the medical literature. Since severe hyponatremia can produce significant neurologic damage and is associated with a high mortality rate, clinicians should be aware that this complication may occur during amiodarone therapy.

Extracorporeal photopheresis: a review.

Extracorporeal phototherapy (ECP) is a therapeutic approach based on the biological effect of psoralen 8-methoxypsoralen (8-MOP) and ultraviolet light A (UVA) on mononuclear cells collected by apheresis, and reinfused into the patient. Photopheresis is widely used for the treatment of patients with advanced cutaneous T-cell lymphoma (CTLC). Evidence suggests that it prolongs life, and also induces 50-75% response rates. In addition, more and more reports indicate that photopheresis is a potent agent in the therapy of acute allograft rejection among cardiac, lung and renal transplant recipients. There are increasing amounts of data showing that patients with chronic graft versus host disease benefit from this therapy. Likewise, there are indications that there may be a potential role for ECP in the therapy of certain autoimmune diseases resistant to conventional therapy. The mechanism of this treatment is likely due to the induction of anticlonotypic immunity directed against pathogenic clones of T lymphocytes. Treatment induces apoptotic death of pathogenic T-cells, and it is postulated that activation of antigen-presenting cells has important effects in this process.

Hypopituitarism after aseptic cavernous sinus thrombosis.

A 44-year-old man developed aseptic thrombosis of the cavernous sinuses. He recovered but 3 months later presented a clinical and laboratory picture of pituitary insufficiency. After 3 years of hormonal replacement therapy, he was in good physical condition.

Age-related changes in upper airway muscles morphological and oxidative properties.

Obstructive sleep apnea (OSA) is a common disorder of the middle aged and elderly. It results from the decrease in upper airway muscle (UAM) tone that occurs during sleep. It is unclear whether age-related changes in UAM could constitute a contributory mechanism to the increased prevalence of OSA with increasing age, and previous papers evaluating the effects of aging on UAM in rats reported conflicting results. In the present study, we compared, in four age groups of Wistar rats (6-24 months), fiber-type distribution, mean cross-sectional fiber area and succinate dehydrogenase optical density of dilating and non-dilating UAM, and the diaphragm. Succinate dehydrogenase optical density, a marker of oxidative capacity, decreased significantly after the age of 6 months in all muscles (except for the sternohyoid), particularly in the genioglossus, the main tongue protrudor. In this muscle, we also found a significant decrease in type IIa and an increase in IIb fibers after the age of 18 months. Age-related changes in fiber-type distribution in other muscles were mostly insignificant. Dilating UAM could not be distinguished from their non-dilating neighboring muscles by their histochemical properties or aging-related changes. The aging-related changes observed in the present study may decrease UAM endurance, particularly that of the main tongue protrudor, the genioglossus.

Massive thrombosis as a result of triple infestation of the pulmonary arterial circulation by Ascaris, Candida, and Mucor.

A 35-year-old man with a brief history of dyspnea and fever experienced rapid progressive respiratory distress and died shortly after being hospitalized. Postmortem examination revealed thrombotic occlusion of the pulmonary tree; the thrombotic material showed Ascaris lumbricoides, Candida albicans, and Mucor. This rare coincidence is an unexpected complication of ascariasis that has not been described previously.

The effect of congesting cuffs on the echo-phonocardiographic findings in mitral valve prolapse.

Changes in left ventricular volume appear to be important in changing the timing and duration of mitral valve prolapse. In this study, simultaneous phonocardiograms and echocardiograms were recorded in 16 patients with late systolic mitral valve prolapse before and after the inflation of congesting cuffs (tourniquets) on the upper and lower extremities. The tourniquet application, known to reduce the venous return, caused a statistically significant movement of the phonocardiographic recorded click toward the first heart sound, associated with reduction of the echocardiographic left and right ventricular and left atrial dimensions. These findings confirm the relationship between the mitral valve prolapse and left ventricular dimension and suggest that a decrease in left ventricular volume is a tenable explanation for the earlier onset of prolapse.

Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischemic heart disease.

Selective beta 2-agonist aerosols may produce significant cardiovascular effects. In the present study we used Holter monitoring to compare the arrhythmogenic effects of inhaled terbutaline (TE), a beta 2-agonist, with that of ipratropium bromide (IB), a nonabsorbable cholinergic drug. Fourteen patients with concomitant obstructive lung disease, ischemic heart disease, and complaints of postinhalation palpitations were studied in a random, double-blind, cross-over fashion. Both drugs significantly improved vital capacity and FEV1. Heart rate and the frequency of premature beats were not significantly affected by the bronchodilators. We conclude that no clear connection between inhaled bronchodilators and arrhythmias could be demonstrated.

Localized Wegener's granulomatosis relapsing as diffuse massive intra-alveolar hemorrhage.

In a 75-year-old patient presenting with a solitary pulmonary mass, a localized form of Wegener's granulomatosis was diagnosed after lobectomy. In the absence of extrapulmonary manifestations and after a benign postoperative course, the patients was discharged without medical treatment. Three months later, diffuse alveolar hemorrhage developed abruptly, necessitating mechanical ventilation, and was followed by cardiac complications and a fatal outcome. This case and another previously reported strongly suggest the need for medical treatment in patients with a localized form of pulmonary Wegener's granulomatosis, even when complete remission after surgical resection of the lung lesion seems to have been achieved.

Effect of hypercapnia and PEEP on expiratory muscle EMG and shortening.

The present study examined the effects of hypercapnia and positive end-expiratory pressure (PEEP) on the electromyographic (EMG) activity and tidal length changes of the expiratory muscles in 12 anesthetized, spontaneously breathing dogs. The integrated EMG activity of both abdominal (external oblique, internal oblique, rectus abdominis, and transverse abdominis) and thoracic (triangularis sterni, internal intercostal) expiratory muscles increased linearly with increasing PCO2 and PEEP. However, with both hypercapnia and PEEP, the percent increase in abdominal muscle electrical activity exceeded that of thoracic expiratory muscle activity. Both hypercapnia and PEEP increased the tidal shortening of the external oblique and rectus abdominis muscles. Changes in tidal length correlated closely with simultaneous increases in muscle electrical activity. However, during both hypercapnia and PEEP, length changes of the external oblique were significantly greater than those of the rectus abdominis. We conclude that both progressive hypercapnia and PEEP increase the electrical activity of all expiratory muscles and augment their tidal shortening but produce quantitatively different responses in the several expiratory muscles.

Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters.

Costal strips of diaphragmatic muscle obtained from animals with elastase-induced emphysema generate maximum tension at significantly shorter muscle fiber lengths than muscle strips from control animals. The present study examined the consequences of alterations in the length-tension relationship assessed in vitro on the pressure generated by the diaphragm in vivo. Transdiaphragmatic pressure (Pdi) and functional residual capacity (FRC) were measured in 22 emphysematous and 22 control hamsters 4-5 mo after intratracheal injection of pancreatic elastase or saline, respectively. In 12 emphysematous and 12 control hamsters Pdi was also measured during spontaneous contractions against an occluded airway. To allow greater control over muscle excitation, Pdi was measured during bilateral tetanic (50 Hz) electrical stimulation of the phrenic nerves in 10 emphysematous and 10 control hamsters. Mean FRC in the emphysematous hamsters was 183% of the value in control hamsters (P less than 0.01). During spontaneous inspiratory efforts against a closed airway the highest Pdi generated at FRC tended to be greater in control than emphysematous hamsters. When control hamsters were inflated to a lung volume approximating the FRC of emphysematous animals, however, peak Pdi was significantly greater in emphysematous animals (70 +/- 6 and 41 +/- 8 cmH2O; P less than 0.05). With electrophrenic stimulation, the Pdi-lung volume curve was shifted toward higher lung volumes in emphysematous hamsters. Pdi at all absolute lung volumes at and above the FRC of emphysematous hamsters was significantly greater in emphysematous compared with control animals. Moreover, Pdi continued to be generated by emphysematous hamsters at levels of lung volume where Pdi of control subjects was zero.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex effect of esophageal distension on respiratory muscle activity and pressure.

The electrical activity of the respiratory skeletal muscles is altered in response to reflexes originating in the gastrointestinal tract. The present study evaluated the reflex effects of esophageal distension (ED) on the distribution of motor activity to both inspiratory and expiratory muscles of the rib cage and abdomen and the resultant changes in thoracic and abdominal pressure during breathing. Studies were performed in 21 anesthetized spontaneously breathing dogs. ED was produced by inflating a balloon in the distal esophagus. ED decreased the activity of the costal and crural diaphragm and external intercostals and abolished all preexisting electrical activity in the expiratory muscles of the abdominal wall. On the other hand, ED increased the activity of the parasternal intercostals and expiratory muscles located in the rib cage (i.e., triangularis sterni and internal intercostal). All effects of ED were graded, with increasing distension exerting greater effects, and were eliminated by vagotomy. The effect of increases in chemical drive and lung inflation reflex activity on the response to ED was examined by performing ED while animals breathed either 6.5% CO2 or against graded levels of positive end-expiratory pressure (PEEP), respectively. Changes in respiratory muscle electrical activity induced by ED were similar (during 6.5% CO2 and PEEP) to those observed under control conditions. We conclude that activation of mechanoreceptors in the esophagus reflexly alters the distribution of motor activity to the respiratory muscles, inhibiting the muscles surrounding the abdominal cavity and augmenting the parasternals and expiratory muscles of the chest wall.

Expiratory muscle activity during pulmonary edema in the anesthetized dog.

The present study evaluated the reflex response of the expiratory muscles to pulmonary congestion and edema. The electromyograms of two thoracic and four abdominal expiratory muscles were recorded in 12 anesthetized dogs. Pulmonary edema was induced by rapid saline infusion in six dogs and injection of oleic acid into the pulmonary circulation in the remaining six dogs. Both forms of pulmonary edema reduced pulmonary compliance, interfered with gas exchange, and induced a rapid and shallow breathing pattern. The electrical activity of all abdominal muscles was suppressed during both forms of pulmonary edema. In contrast, the electromyogram activity of the thoracic expiratory muscles was not significantly affected by pulmonary edema. Acute pulmonary arterial hypertension produced in two dogs by inflating a balloon in the left atrium had no effect on ventilation or expiratory muscle electrical activity. In two vagotomized dogs, pulmonary edema did not inhibit the expiratory muscles. We conclude that pulmonary edema suppresses abdominal but not thoracic expiratory muscle activity by vagal reflex pathway(s). Extravasation of fluid into the lung appears to be more important than an increase in pulmonary vascular pressure in eliciting this response.