Arie Oliven

Implanted upper airway stimulation device for obstructive sleep apnea

Previous feasibility studies have shown that electrical stimulation of the hypoglossal nerve can improve obstructive sleep apnea (OSA). The current study examined the safety and preliminary effectiveness of a second generation device, the Upper Airway Stimulation (UAS) system, and identified baseline predictors for therapy success.

Sublingual electrical stimulation of the tongue during wakefulness and sleep.

Pharyngeal obstruction in patients with obstructive sleep apnea (OSA) is thought to result from decreased upper airway muscle tone during sleep. The goal of the present study was to estimate the role of the tongue muscles in maintaining pharyngeal patency during sleep. Using non-invasive, sub-lingual surface electrical stimulation (ES), we measured tongue protrusion force during wakefulness and upper airway resistance during sleep in seven healthy subjects and six patients with OSA. During wakefulness, ES produced similar protrusion forces in healthy subjects and patients with OSA. ES of the anterior sublingual surface, causing preferential contraction of the genioglossus, resulted in smaller effects than combined ES of the anterior and lateral surface, which also stimulated tongue retractors. During sleep, trans-pharyngeal resistance decreased and peak inspiratory flow rate increased from 319+/-24 to 459+/-27 and from 58+/-16 to 270+/-35 ml/sec for healthy subjects and OSA patients, respectively (P<0.001). However, ES was usually unsuccessful in reopening the upper airway in the presence of complete apneas. We conclude that non-invasive ES of the tongue improves flow dynamics during sleep. Combined activation of tongue protrusors and retractors may have a beneficial mechanical effect. The magnitude of responses observed suggests that in addition to the stimulated muscles, other muscles and/or forces have a substantial impact on pharyngeal patency.

Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure.

Background: Several studies have shown that serum levels of tumor necrosis factor‐α (TNF) are significantly elevated in patients with acute and chronic liver diseases, where these elevations are independent of the etiology of the underlying disease. Serum levels of TNF are significantly higher in patients with cirrhosis than in those without cirrhosis, reaching the highest levels in decompensated cirrhosis. It has also been shown that plasma levels of TNF correlate with the severity of hepatic encephalopathy (HE) in fulminant hepatic failure. However, still there are no published data regarding the relationship between blood levels of TNF and the presence or severity of HE in patients with chronic liver failure.

Effect of genioglossus contraction on pharyngeal lumen and airflow in sleep apnoea patients

The purpose of the present study was to quantify the mechanical effect of genioglossus stimulation on flow mechanics and pharyngeal cross-sectional area in patients with obstructive sleep apnoea, and to identify variables that determine the magnitude of the respiratory effect of tongue protrusion. The pressure/flow and pressure/cross-sectional area relationships of the velo- and oropharynx were assessed in spontaneously breathing propofol-anaesthetised subjects before and during genioglossus stimulation. Genioglossus contraction decreased the critical pressure significantly from 1.2±3.3 to -0.7±3.8 cmH2O, with individual decreases ranging -0.6–5.9 cmH2O. Pharyngeal compliance was not affected by genioglossus contraction. The pharyngeal response to genioglossus stimulation was related to the magnitude of advancement of the posterior side of the tongue, but not to the severity of sleep apnoea, critical pressure, compliance or the shape and other characteristics of the velopharynx. Genioglossus contraction enlarges both the velo- and the oropharynx and lowers the critical pressure without affecting pharyngeal stiffness. The response to genioglossus stimulation depends upon the magnitude of tongue protrusion achieved rather than on inherent characteristics of the patient and their airway.

Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure

BACKGROUND. We have recently demonstrated that in humans, circulating levels of tumor necrosis factor‐α (TNF) correlate positively with severity of hepatic encephalopathy (HE) due to chronic liver failure. AIM. The main aim of this larger population study is to determine the relationship between TNF and ammonia in patients with HE and chronic liver failure due to liver cirrhosis. METHODS. Circulating levels of TNF and ammonia were measured in 108 patients with liver cirrhosis due to various etiologies in various clinical grades of HE (grades 0–4). TNF concentrations were measured in venous serum using commercially available solid‐phase high sensitivity enzyme‐linked immunosorbent assay. Ammonia levels were determined in venous plasma by the enzymatic method, using the glutamate dehydrogenase reaction. RESULTS. The mean±SEM values of circulating levels of TNF and ammonia at presentation in patients with grade 0 of HE (n = 30) were 3.89±0.2 pg/mL and 49.8±2.8 µg/mL respectively, in patients with grade 1 of HE (n = 26) were 8.56±0.34 pg/mL and 101.6±6.5 µg/mL respectively, in patients with grade 2 of HE (n = 22) were 11.59±0.48 pg/mL and 160.3±10.7 µg/mL respectively, in patients with grade 3 of HE (n = 20) were 19.98±0.94 pg/mL and 228.8±16.1 µg/mL respectively, and in patients with grade 4 of HE (n = 10) were 51.53±8.59 pg/mL and 284.2±20.3 µg/mL respectively. A significant positive correlation was found between circulating levels of TNF and those of ammonia (r = 0.62, P<0.0001), and also between circulating levels of both substances and severity of HE in these patients (r = 0.95, P<0.0001, and r = 0.9, P<0.0001 respectively). TNF and ammonia were both significant independent predictors of severity of HE (P<0.0001 for both variables). CONCLUSION. The results of this study demonstrate a significant relationship between TNF and ammonia in patients with chronic liver failure and HE, and so strengthen the suggestion that TNF could be strongly involved in the pathogenesis of HE in these patients. Hence, we suggest a new theory in the pathogenesis of HE, the ‘TNF theory’.

Improved Upper Airway Patency Elicited by Electrical Stimulation of the Hypoglossus Nerves

The present study evaluated the mechanisms by which upper airway (UAW)-dilating muscle contraction, elicited by hypoglossus nerve (HGN) stimulation, improved UAW patency. Pressure-flow (P-V) relationships of the isolated UAW as well as the negative intraluminal pressures required to cause UAW collapse were assessed before and during electrical stimulation of the HGN in 8 anesthetized, ventilated dogs. Sectioning of the HGN shifted the P-V relationship to the left, while electrical stimulation resulted in a substantial shift of the curve to the right, indicating UAW dilatation. UAW resistance decreased from 9.0 +/- 1.5 to 0.3 +/- 0.1 cm H2O.1(-1).s during HGn stimulation (p < 0.01). The magnitude of negative intraluminal pressure at which UAW collapse occurred (the critical pressure) increased from -2.7 +/- 0.7 to -13.2 +/- 2.1 cm H2O (p < 0.002). The increase in UAW conductance and stability raised the maximal flow which could be sustained without collapse from 0.28 +/- 0.07 to 2.07 +/- 0.35 l/s during HGN stimulation (p < 0.001). These findings indicate that in the anesthetized dog, UAW muscle contraction improves UAW patency both by dilating the UAW and by stiffening its walls.

Effect of upper airway muscle contraction on supraglottic resistance and stability

The activation of upper airway (UAW) muscles is believed to increase UAW patency to air flow. To evaluate the mechanisms by which UAW muscles act to prevent UAW collapse, pressure-flow relationships of the isolated UAW as well as the negative pressure required to cause UAW collapse (Pcrit) were assessed before and during electrical stimulation of four UAW muscle pairs in anesthetized dogs. Stimulation of each of the muscles shifted the pressure-flow curve toward lower pressures for any given flow rate, indicating UAW dilatation. UAW resistance decreased from 7.9 +/- 0.6 to 0.4 +/- 0.1, 2.7 +/- 0.6, 2.3 +/- 0.8 and to 4.8 +/- 1.5 cmH2O.L-1.sec during genioglossus, geniohyoid, sternothyroid and sternohyoid stimulation respectively (P < 0.01 in all cases). However, only genioglossus stimulation significantly increased Pcrit (from -3.4 +/- 0.6 to -12.0 +/- 1.8 cmH2O, P < 0.001). Relaxation of the genioglossus thus appears to produce the main impediment to air flow through the UAW, and contraction of this muscle improves UAW patency both by dilating the supraglottic airway and by stiffening its walls.

Dependency of upper airway patency on head position: the effect of muscle contraction.

In the present study we examined the effect of flexion and extension of the head on upper airway (UAW) patency in anesthetized dogs, and compared the dilatory and stabilizing effects of electrically stimulated UAW muscles at the different head positions. Flexion of the head increased UAW resistance (Ruaw) and reduced maximal flow (Vmax), but had little effect on the negative pressure at which UAW collapse occurred (Pcrit). Extension of the head, on the other hand, resulted in more negative Pcrit values and increased Vmax without significantly affecting Ruaw. Electrically induced UAW muscle contraction affected the pressure-flow curve and Ruaw, as well as Pcrit. Changing head position had a substantial effect on the dilatory and stabilizing effect of the various UAW muscles. However, independent of head position, genioglossus stimulation was most effective in reducing Ruaw and increasing Pcrit. We conclude that in the anesthetized, supine dog, head position affects the mechanical properties of the UAW and the effects of UAW muscle contraction.

Interacting effects of genioglossus stimulation and mandibular advancement in sleep apnea

Both mandibular advancement (MA) and stimulation of the genioglossus (GG) have been shown to improve upper airway patency, but neither one achieves the effect of continuous positive airway pressure (CPAP) treatment. In the present study we assessed the combined effect of MA and GG stimulation on the relaxed pharynx in patients with obstructive sleep apnea (OSA). We evaluated responses of upper airway pressure-flow relationships and endoscopically determined pharyngeal cross-sectional area to MA and electrical stimulation of the GG in 14 propofol-anesthetized OSA patients. Measurements were undertaken at multiple levels of CPAP, enabling calculation of the critical closing pressure (Pcrit), upstream resistance (Rus), and pharyngeal compliance. GG stimulation, MA, and the combination of both shifted the pressure:flow relationships toward higher flow levels, resulting in progressively lower Pcrit (from baseline of 2.9 +/- 2.2 to 0.9 +/- 2.5, -1.4 +/- 2.9, and -4.2 +/- 3.3 cmH(2)O, respectively), without significant change in Rus. DeltaPcrit during GG stimulation was significantly larger during MA than under baseline conditions (-2.8 +/- 1.4 vs. -2.0 +/- 1.4 cmH(2)O, P = 0.011). Combining the effect of GG stimulation with MA lowered Pcrit below 0 in all patients and restored pharyngeal patency to a level that enabled flow above the hypopnea level in 10/14 of the patients. Velopharyngeal compliance was not affected by either manipulation. We conclude that the combined effect of MA and GG stimulation is additive and may act in synergy, preventing substantial flow limitation of the relaxed pharynx in most OSA patients.

Termination of intractable hiccups with digital rectal massage.

Abstract. A 60‐year‐old man with acute pancreatitis developed persistent hiccups after insertion of a nasogastric tube. Removal of the latter did not terminate the hiccups which had also been treated with different drugs, and several manoeuvres were attempted, but with no success. Digital rectal massage was then performed resulting in abrupt cessation of the hiccups. Recurrence of the hiccups occurred several hours later, and again, they were terminated immediately with digital rectal massage. No other recurrences were observed. This is the second reported case associating cessation of intractable hiccups with digital rectal massage. We suggest that this manoeuvre should be considered in cases of intractable hiccups before proceeding with pharmacological agents.