[Obesity-hypoventilation syndrome]. / Syndrome obésité-hypoventilation.

INTRODUCTION: The obesity-hypoventilation syndrome (OHS), or alveolar hypoventilation in the obese, has been described initially as the "Pickwickian syndrome". It is defined as chronic alveolar hypoventilation (PaO2<70 mmHg, PaCO2 > or =45 mmHg) in obese patients (body mass index>30 kg/m2) who have no other respiratory disease explaining the hypoxemia-hypercapnia. BACKGROUND: The large majority of obese subjects are not hypercapnic, even in case of severe obesity (>40 kg/m2). There are three principal causes, which can be associated, explaining alveolar hypoventilation in obese subjects: high cost of respiration and weakness of the respiratory muscles (probably the major cause), dysfunction of the respiratory centers with diminished chemosensitivity, long-term effects of the repeated episodes of obstructive sleep apneas observed in some patients. The role of leptin (hormone produced by adipocytes) in the pathogenesis of this syndrome, has been recently advocated. OHS is generally observed in subjects over 50 years. Its prevalence has markedly increased in recent years, probably due to the present "epidemic" of obesity. The diagnosis is often made after an episode of severe respiratory failure. Comorbidities, favored by obesity, are very frequent: systemic hypertension, left heart diseases, diabetes. VIEWPOINT: OHS must be distinguished from obstructive sleep apnea syndrome (OSAS) even if the two conditions are often associated. OSAS may be absent in certain patients with OHS (20% of the patients in our experience). On the other hand obesity may be absent in certain patients with OSAS. CONCLUSION: Losing weight is the "ideal" treatment of OHS but in fact it cannot be obtained in most patients. Nocturnal ventilation (continuous positive airway pressure and mainly bilevel non invasive ventilation) is presently the best treatment of OHS and excellent short and long-term results on symptoms and arterial blood gases have been recently reported.

Hydrogen sulfide as an oxygen sensor in trout gill chemoreceptors.

O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine beta-synthase and cystathionine gamma-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a PO2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar approximately 10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to PO2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues.

Effects of chemoreflexes on hyperthermic hyperventilation and cerebral blood velocity in resting heated humans.

We tested the hypothesis that hyperthermic hyperventilation in part reflects enhanced chemoreceptor ventilatory O(2) drive, and that the resultant hypocapnia attenuates ventilatory responses and/or middle cerebral artery mean blood velocity (MCAV(mean)) in resting humans. Eleven healthy subjects were passively heated for 50-80 min, causing oesophageal temperature (T(oes)) to increase by 1.6 degrees C. During heating, minute ventilation increased (P < 0.05), while end-tidal CO(2) pressure (P(ET,CO(2))) and MCAV(mean) declined. A hyperoxia test in which three breaths of hyperoxic air were inspired was performed once before heating and three times during the heating. When we observed hypocapnia (P(ET,CO(2)) below 40 mmHg), P(ET,CO(2)) was restored to the eucapnic level by adding 100% CO(2) to the inspired air immediately before the last two tests. Minute ventilation was significantly reduced by hyperoxia, and that reduction gradually increased with increasing T(oes). However, the percentage decrease in from the normoxic level was small (20-29%) and unchanged during heating. When P(ET,CO(2)) was restored to eucapnic levels, was unchanged, but MCAV(mean) was partly restored to the level seen prior to heating (28.1% restoration at T(oes) 37.6 degrees C and 38.1% restoration at T(oes) 38.0 degrees C). These findings suggest that although hyperthermia increases chemoreceptor ventilatory O(2) drive in resting humans, the relative contribution of the chemoreceptor ventilatory O(2) drive to hyperthermic hyperventilation is small ( approximately 20%) and unaffected by increasing core temperature. Moreover, hypocapnia induced by hyperthermic hyperventilation reduces cerebral blood flow but not ventilatory responses.

Some aspects of clinical relevance in the maturation of respiratory control in infants.

Two reflex mechanisms important for survival are discussed. Brain stem and cardiovascular mechanisms that are responsible for recovery from severe hypoxia (autoresuscitation) are important for survival in acutely hypoxic infants and adults. Failure of this mechanism may be important in sudden infant death syndrome (SIDS), because brain stem-mediated hypoxic gasping is essential for successful autoresuscitation and because SIDS infants appear to attempt to autoresuscitate just before death. A major function of another mechanism is to protect the airway from fluid aspiration. The various components of the laryngeal chemoreflex (LCR) change during maturation. The LCR is an important cause of prolonged apneic spells in infants. Consequently, it also may have a role in causing SIDS. Maturational changes and/or inadequacy of this reflex may be responsible for pulmonary aspiration and infectious pneumonia in both children and adults.

Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats.

Ventilatory long-term facilitation (LTF; defined as gradual increase of minute ventilation following repeated hypoxic exposures) is well described in adult mammals and is hypothesized to be a protective mechanism against apnea. In newborns, LTF is absent during the first postnatal days, but its precise developmental pattern is unknown. Accordingly, this study describes this pattern of postnatal development. Additionally, we tested the hypothesis that chronic intermittent hypoxia (CIH) from birth alters this development. LTF was estimated in vivo using whole body plethysmography by exposing rat pups at postnatal days 1, 4, and 10 (P1, P4, and P10) to 10 brief hypoxic cycles (nadir 5% O2) and respiratory recordings during the following 2 h (recovery, 21% O2). Under these conditions, ventilatory LTF (gradual increase of minute ventilation during recovery) was clearly expressed in P10 rats but not in P1 and P4. In a second series of experiments, rat pups were exposed to CIH during the first 10 postnatal days (6 brief cyclic exposures at 5% O2 every 6 min followed by 1 h under normoxia, 24 h a day). Compared with P10 control rats, CIH enhanced hypoxic ventilatory response (estimated during the hypoxic cycles) specifically in male rat pups. Ventilatory LTF was drastically reduced in P10 rats exposed to CIH, which was associated with higher apnea frequency during recovery. We conclude that CIH from birth enhances hypoxic chemoreflex and disrupts LTF development, thus likely contributing to increase apnea frequency.

Adaptations in autonomic function during exercise training in heart failure.

Although neurohumoral excitation is the hallmark of heart failure (HF), the mechanisms underlying this alteration are not entirely known. Abnormalities in several systems contribute to neurohumoral excitation in HF, including arterial and cardiopulmonary baroreceptors, central and peripheral chemoreceptors, cardiac chemoreceptors, and central nervous system abnormalities. Exercise intolerance is characteristic of chronic HF, and growing evidence strongly suggests that exercise limitation in patients with chronic HF is not due to elevated filling pressures or inadequate cardiac output during exercise, but instead due to skeletal myopathy. Several lines of evidence suggest that sympathetic excitation contributes to the skeletal myopathy of HF, since sympathetic activity mediates vasoconstriction at rest and during exercise likely restrains muscle blood flow, arteriolar dilatation, and capillary recruitment, leading to underperfused areas of working muscle, and areas of muscle ischemia, release of reactive oxygen species (ROS), and inflammation. Although controversial, either unmyelinated, metabolite-sensitive afferent fibers, and/or myelinated, mechanosensitive afferent fibers in skeletal muscle underlie the exaggerated sympathetic activity in HF. Exercise training has emerged as a unique non-pharmacological strategy for the treatment of HF. Regular exercise improves functional capacity and quality of life, and perhaps prognosis in chronic HF patients. Recent studies have provided convincing evidence that these benefits in chronic HF patients are mediated by significant reduction in central sympathetic outflow as a consequence of improvement in arterial and chemoreflex controls, and correction of central nervous system abnormalities, and increase in peripheral blood flow with reduction in cytokines and increase in mass muscle.

Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold divers.

Repeated hypoxemia in obstructive sleep apnea patients increases sympathetic activity, thereby promoting arterial hypertension. Elite breath-holding divers are exposed to similar apneic episodes and hypoxemia. We hypothesized that trained divers would have increased resting sympathetic activity and blood pressure, as well as an excessive sympathetic nervous system response to hypercapnia. We recruited 11 experienced divers and 9 control subjects. During the diving season preceding the study, divers participated in 7.3 +/- 1.2 diving fish-catching competitions and 76.4 +/- 14.6 apnea training sessions with the last apnea 3-5 days before testing. We monitored beat-by-beat blood pressure, heart rate, femoral artery blood flow, respiration, end-tidal CO(2), and muscle sympathetic nerve activity (MSNA). After a baseline period, subjects began to rebreathe a hyperoxic gas mixture to raise end-tidal CO(2) to 60 Torr. Baseline MSNA frequency was 31 +/- 11 bursts/min in divers and 33 +/- 13 bursts/min in control subjects. Total MSNA activity was 1.8 +/- 1.5 AU/min in divers and 1.8 +/- 1.3 AU/min in control subjects. Arterial oxygen saturation did not change during rebreathing, whereas end-tidal CO(2) increased continuously. The slope of the hypercapnic ventilatory and MSNA response was similar in both groups. We conclude that repeated bouts of hypoxemia in elite, healthy breath-holding divers do not lead to sustained sympathetic activation or arterial hypertension. Repeated episodes of hypoxemia may not be sufficient to drive an increase in resting sympathetic activity in the absence of additional comorbidities.

Laryngeal apnea in rat pups: effects of age and body temperature.

In neonatal mammals of many species, including human infants, apnea and other reflex responses frequently arise from stimulation of laryngeal receptors by ingested or regurgitated liquids. These reflexes, mediated by afferents in the superior laryngeal nerves (SLNs), are collectively known as the laryngeal chemoreflex (LCR) and are suspected to be responsible for some cases of the sudden infant death syndrome (SIDS). The LCR is strongly enhanced by mild increases in body temperature in decerebrate piglets, a finding that is of interest because SIDS victims are often found in overheated environments. Because of the experimental advantages of studying reflex development and mechanisms in neonatal rodents, we have developed methods for eliciting laryngeal apnea in anesthetized rat pups and have examined the influence of mild hyperthermia in animals ranging in age from 3 to 21 days. We found that apnea and respiratory disruption, elicited either by intralaryngeal water or by electrical stimulation of the SLN, occurred at all ages studied. Raising body temperature by 2-3 degrees C prolonged the respiratory disturbance in response to either stimulus. This effect of hyperthermia was prominent in the youngest animals and diminished with age. We conclude that many studies of the LCR restricted to larger neonatal animals in the past can be performed in infant rodents using appropriate methods. Moreover, the developmental changes in the LCR and in the thermal modulation of the LCR seem to follow different temporal profiles, implying that distinct neurophysiological processes may mediate the LCR and thermal prolongation of the LCR.

Effects of enoximone on peripheral and central chemoreflex responses in humans.

cAMP plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication enoximone increases peripheral chemoreflex function in humans. In a single-blind, randomized, placebo-controlled crossover study of 15 men, we measured ventilatory, muscle sympathetic nerve activity, and hemodynamic responses to 5 min of isocapnic hypoxia, 5 min of hyperoxic hypercapnia, and 3 min of isometric handgrip exercise, separated by 1 wk, with enoximone and placebo administration. Enoximone increased cardiac output by 120 +/- 3.7% from baseline (P < 0.001); it also increased the ventilatory response to acute hypoxia [13.6 +/- 1 vs. 11.2 +/- 0.7 l/min at 5 min of hypoxia, P = 0.03 vs. placebo (by ANOVA)]. Despite a larger minute ventilation and a smaller decrease in O(2) desaturation (83 +/- 1 vs. 79 +/- 2%, P = 0.003), the muscle sympathetic nerve response to hypoxia was similar between enoximone and placebo (123 +/- 6 and 117 +/- 6%, respectively, P = 0.28). In multivariate regression analyses, enoximone enhanced the ventilatory (P < 0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (P = 0.13). Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, inasmuch as central chemoreflex and isometric handgrip responses were not altered by enoximone.

Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans.

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.

Unilateral microdialysis of gabazine in the dorsal medulla reverses thermal prolongation of the laryngeal chemoreflex in decerebrate piglets.

The laryngeal chemoreflex (LCR) is elicited by water in the larynx and leads to apnea and respiratory disruption in immature animals. The LCR is exaggerated by the elevation of brain temperature within or near the nucleus of the solitary tract (NTS) in decerebrate piglets. Thermal prolongation of reflex apnea elicited by superior laryngeal nerve stimulation is reduced by systemic administration of GABA(A) receptor antagonists. Therefore, we tested the hypothesis that microdialysis within or near the NTS of gabazine, a GABA(A) receptor antagonist, would reverse thermal prolongation of the LCR. We examined this hypothesis in 21 decerebrate piglets (age 3-13 days). We elicited the LCR by injecting 0.1 ml of water into the larynx before and after each piglet's body temperature was elevated by approximately 2.5 degrees C and before and after 2-5 mM gabazine was dialyzed unilaterally and focally in the medulla. Elevated body temperature failed to prolong the LCR in one piglet, which was excluded from analysis. Elevated body temperature prolonged the LCR in all the remaining animals, and dialysis of gabazine into the region near the NTS (n = 10) reversed the thermal prolongation of the LCR even though body temperature remained elevated. Dialysis of gabazine in other medullary sites (n = 10) did not reverse thermal prolongation of the LCR. Gabazine had no consistent effect on baseline respiratory activity during hyperthermia. These findings are consistent with the hypothesis that hyperthermia activates GABAergic mechanisms in or near the NTS that are necessary for the thermal prolongation of the LCR.

Prediction of atrial fibrillation with atrial late potentials and pathological chemoreflexsensitivity.

BACKGROUND: Atrial fibrillation (AF) is a very common arrhythmia that often causes the serious complication of a stroke. OBJECT: The aim was to evaluate the utility of pathological chemoreflexsensitivity (PCHRS) and atrial late potentials (ALP) to predict AF in follow-up. METHODS: We investigated a prospective study on the basis of our observation about a PCHRS and ALP in paroxysmal AF. The PCHRS was predefined as a chemoreflexsensitivity below 3.0 ms/mmHg and ALP were predefined as a filtered P-wave duration > or =120 ms and a root mean square voltage of the last 20 ms of the P-wave < or =3.5 microV. A P-wave triggered P-wave signal averaged electrocardiograph (ECG) and chemoreflexsensitivity was performed on 250 consecutive patients who were divided into four groups. Group I consisted of patients with ALP and PCHRS, patients of group II had only ALP, a PCHRS was only present in group III, and patients of group IV had neither ALP nor PCHRS. RESULTS: During the mean follow-up of 37.8 months AF was observed in 10 patients (4%). The patients of the four groups were similar according to clinical baseline characteristics. The incidence of AF was higher in group I (18% of patients) than in group II (6% of patients, P = 0.229) and significantly higher than in group III (3% of patients, P = 0.034) or group IV (1% of patients, P < 0.0001). Patients with ALP and PCHRS showed a 33-fold risk (P < 0.001) for the onset AF. CONCLUSIONS: The results of our study suggest that the probability of AF could be predicted with a P-wave signal averaged ECG and an analysis of chemoreflexsensitivity. The predictive power of the combination of ALP and PCHRS seemed not high enough for risk stratification.

[Diagnosis of olfactory disorders--clinical standards and research]. / Diagnostik von Riechstörungen--Standards und Forschung.

Olfactory dysfunction has been reported to affect about 79,000 patients who were treated annually in German ORL-hospitals. The incidence of olfactory dysfunctions emphasizes the need for diagnostic strategies. This article features on the dysfunction of human olfaction including neurodegenerative diseases. Standard procedures for the psychophysical and objective assessment of olfactory function are presented. Current diagnostic imaging techniques for routine use and scientific approaches are discussed.

Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity.

BACKGROUND: Human breathing is regulated by feedback and feed-forward control mechanisms, allowing a strict matching between metabolic needs and the uptake of oxygen in the lungs. The most important control mechanism, the metabolic ventilatory control system, is fine-tuned by two sets of chemoreceptors, the peripheral chemoreceptors in the carotid bodies (located in the bifurcation of the common carotid arteries) and the central CO2 chemoreceptors in the ventral medulla. Animal data indicate that resection of the carotid bodies results, apart from the loss of the peripheral chemoreceptors, in reduced activity of the central CO2 sensors. We assessed the acute and chronic effect of carotid body resection in three humans who underwent bilateral carotid body resection (bCBR) after developing carotid body tumors. METHODS AND FINDINGS: The three patients (two men, one woman) were suffering from a hereditary form of carotid body tumors. They were studied prior to surgery and at regular intervals for 2-4 y following bCBR. We obtained inspired minute ventilation (Vi) responses to hypoxia and CO2. The Vi-CO2 responses were separated into a peripheral (fast) response and a central (slow) response with a two-compartment model of the ventilatory control system. Following surgery the ventilatory CO2 sensitivity of the peripheral chemoreceptors and the hypoxic responses were not different from zero or below 10% of preoperative values. The ventilatory CO2 sensitivity of the central chemoreceptors decreased by about 75% after surgery, with peak reduction occurring between 3 and 6 mo postoperatively. This was followed by a slow return to values close to preoperative values within 2 y. During this slow return, the Vi-CO2 response shifted slowly to the right by about 8 mm Hg. CONCLUSIONS: The reduction in central Vi-CO2 sensitivity after the loss of the carotid bodies suggests that the carotid bodies exert a tonic drive or tonic facilitation on the output of the central chemoreceptors that is lost upon their resection. The observed return of the central CO2 sensitivity is clear evidence for central plasticity within the ventilatory control system. Our data, although of limited sample size, indicate that the response mechanisms of the ventilatory control system are not static but depend on afferent input and exhibit a large degree of restoration or plasticity. In addition, the permanent absence of the breathing response to hypoxia after bCBR may aggravate the pathological consequences of sleep-disordered breathing.

Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice.

We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO(2)) or hypoxic (15 or 10% O(2)) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX- KO mice (0.22 +/- 0.03 mlxmin(-1)xg(-1)x% CO(2)(-1)) was significantly blunted compared with that in WT mice (0.51 +/- 0.05 mlxmin(-1)xg(-1)x% CO(2)(-1)). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 +/- 0.03 mlxmin(-1).g(-1)x% CO(2)(-1) for orexin-A and 0.32 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1) for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1)). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO(2) sensitivity at least during wake periods in mice.

The ontogeny of hemodynamic responses to prolonged umbilical cord occlusion in fetal sheep.

There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses; there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 (n = 12), 0.7 (n = 12), and 0.85 (n = 8) of gestational age (GA; term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord.

Sympathetic chemoreflex responses in obstructive sleep apnea and effects of continuous positive airway pressure therapy.

BACKGROUND: Sympathetic nerve activity is increased in awake and regularly breathing patients with obstructive sleep apnea (OSA). Over time, repetitive hypoxic stress could alter sympathetic chemoreflex function in OSA. METHODS: We determined the responses to acute hypoxia (fraction of inspired oxygen of 0.1, for 5 min), static handgrip exercise, and the cold pressor test (CPT) in 24 patients with OSA (age, 50 +/- 3 years [mean +/- SEM]; apnea-hypopnea index, 47 +/- 6 events per hour) and in 14 age- and weight-matched nonapneic control subjects. Muscle sympathetic nerve activity (MSNA) [peroneal microneurography], BP, and ventilation were monitored. RESULTS: Basal MSNA was higher in OSA patients compared to control subjects (45 +/- 4 bursts per minute vs 33 +/- 4 bursts per minute, respectively; p < 0.05). Furthermore, compared to control subjects, the MSNA responses to hypoxia were markedly enhanced in OSA (p < 0.001). Whereas the ventilatory responses to hypoxia tended to be increased in OSA (p = 0.06), the BP responses did not differ between the groups (p = 0.45). The neurocirculatory reflex responses to handgrip exercise and to the CPT were similar in the two groups (p = not significant). In OSA patients who were retested after 1 to 24 months of continuous positive airway pressure (CPAP) therapy (n = 11), basal MSNA (p < 0.01) and the responses of MSNA to hypoxia (p < 0.01) decreased significantly, whereas the ventilatory responses remained unchanged (p = 0.82). CONCLUSION: These data suggest that the sympathetic responses to hypoxic chemoreflex stimulation are enhanced in OSA and may normalize in part following CPAP therapy.

Interactions between the chemical senses: trigeminal function in patients with olfactory loss.

The intranasal trigeminal and the olfactory system are intimately connected. There is evidence showing that acquired olfactory loss leads to reduced trigeminal sensitivity due to the lack of a central-nervous interaction. Both, the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input which is missing in patients with olfactory loss. On peripheral levels, however, adaptive mechanisms seem to produce an increase in the trigeminal responsiveness of patients with hyposmia or anosmia.

Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs.

Chronic exposure to intermittent hypoxia (CIH) has been used in animals to mimic the arterial hypoxemia that accompanies sleep apnea. Humans with sleep apnea and animals exposed to CIH have elevated blood pressures and augmented sympathetic nervous system responses to acute exposures to hypoxia. To test the hypothesis that exposure to CIH alters neurons within the nucleus of the solitary tract (NTS) that integrate arterial chemoreceptor afferent inputs, we measured whole cell currents induced by activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in enzymatically dispersed NTS neurons from normoxic (NORM) and CIH-exposed rats (alternating cycles of 3 min at 10% O2 followed by 3 min at 21% O2 between 8 AM and 4 PM for 7 days). To identify NTS neurons receiving carotid body afferent inputs the anterograde tracer 4- (4-(dihexadecylamino)styryl-N-methylpyridinum iodide (DiA) was placed onto the carotid body 1 wk before exposure to CIH. AMPA dose-response curves had similar EC50 but maximal responses increased in neurons isolated from DiA-labeled CIH (20.1 +/- 0.8 microM, n = 9) compared with NORM (6.0 +/- 0.3 microM, n = 8) rats. NMDA dose-response curves also had similar EC50 but maximal responses decreased in CIH (8.4 +/- 0.4 microM, n = 8) compared with NORM (19.4 +/- 0.6 microM, n = 9) rats. These results suggest reciprocal changes in the number and/or conductance characteristics of AMPA and NMDA receptors. Enhanced responses to AMPA receptor activation could contribute to enhanced chemoreflex responses observed in animals exposed to CIH and humans with sleep apnea.