The interaction of the upper airway and thermo-metabolism on respiratory rhythm during non-REM sleep in the developing lamb.

This study investigates the role of metabolic rate and of vagal airway mechanisms in sustaining rhythmic breathing in the developing lamb. Fifteen lambs were prepared, at 2 days of age under fluothane anaesthesia, for sequential studies at 4, 14, 30, 45, and 55 days of age. At each age they were maintained at an ambient temperature of 5, 10, 15, 20, 25 and 30 degrees C for at least one hour before measurements were made during N-REM sleep. In 6 lambs at 4 days and in all lambs at older ages the upper airway was by-passed (by opening a tracheal window) for 10-15 minutes at each ambient temperature. Oxygen consumption was unaffected by upper airway by-pass and there were no consistent changes in mean breathing frequency or amplitude, with the exception of shifts to panting at warm ambient temperatures. Breathing pattern was unaffected by upper airway by-pass in lambs at 4 days of age, but at older ages loss of regularity of breathing frequently occurred (up to 47% of 30 days-old lambs at 25 degrees C). This was related to the fall in oxygen consumption with age and to basal values at thermoneutrality, and coincided with lower respiratory rates and increased use of expiratory laryngeal braking. Periodic breathing (and apnea) of a fixed cycle length (9.3 +/- 0.36 s) was a common feature (62%) of the observed breathing dysrhythmia. In young lambs high metabolic rate sustained high frequency rhythmic breathing which was unaffected by upper airway by-pass.(ABSTRACT TRUNCATED AT 250 WORDS)     

The control of thermoregulation in the developing lamb during slow wave sleep

This study investigates the mechanisms involved in adjusting metabolic rate in response to acute changes in ambient temperature close to thermoneutrality during postnatal development. Twelve lambs were prepared for sequential studies at 4, 14, 30, 45 and 55 days of age. During each study they were maintained at ambient temperatures of 5, 10, 15, 20, 25 and 30 degrees C for at least 1 h and until a slow wave sleep epoch was established. Eight lambs completed all studies. In these there was a significant fall in oxygen consumption with age which was independent of ambient temperature. This effect was closely related to a decrease in plasma triiodothyronine concentration that was greatest between 4- and 14-days old lambs and was not associated with a change in the plasma concentration of thyrotrophin or thyroxine. In 4-days old lambs oxygen consumption was increased at ambient temperatures of 5 and 10 degrees C by non-shivering thermogenesis, whilst in 14- and 30-days old lambs this effect was achieved by shivering. On the basis of significant changes in oxygen consumption and/or the occurrence of shivering (lower critical temperature) and panting (upper critical temperature) we have shown that there is a fall in both upper and lower critical temperature with age and a widening of the thermoneutral zone. This was associated with a decrease in the plasma cortisol concentration and heart rate as measured at thermoneutrality, whilst rectal temperature increased from 4 to 30 days of age. The other 4 lambs, 3 of which died between 7 and 17 days of age, had low plasma triiodothyronine concentrations when studied at 4 and/or 14 days of age and their oxygen consumption at thermoneutrality was significantly lower than the normal group at 14 days. Shivering thermogenesis occurred at an earlier age and control of body temperature was less effective. It is concluded that triiodothyronine has an important role in the control of metabolic rate in the developing lamb even to meet modest changes in ambient temperature, and possibly directly in survival.     

Noradrenergic circuit control of non-REM sleep substates

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Selective REM sleep deprivation during daytime. II. Muscle atonia in non-REM sleep

One of the hallmarks of rapid eye movement (REM) sleep is muscle atonia. Here we report extended epochs of muscle atonia in non-REM sleep (MAN). Their extent and time course was studied in a protocol that included a baseline night, a daytime sleep episode with or without selective REM sleep deprivation, and a recovery night. The distribution of the latency to the first occurrence of MAN was bimodal with a first mode shortly after sleep onset and a second mode 40 min later. Within a non-REM sleep episode, MAN showed a U-shaped distribution with the highest values before and after REM sleep. Whereas MAN was at a constant level over consecutive 2-h intervals of nighttime sleep, MAN showed high initial values when sleep began in the morning. Selective daytime REM sleep deprivation caused an initial enhancement of MAN during recovery sleep. It is concluded that episodes of MAN may represent an REM sleep equivalent and that it may be a marker of homeostatic and circadian REM sleep regulating processes. MAN episodes may contribute to the compensation of an REM sleep deficit.     

Adenosine infusion and periodic breathing during sleep.

Intravenously administered adenosine may increase ventilation (VI) and the ventilatory response to CO2 (HCVR). Inasmuch as we have previously hypothesized that those with higher HCVR may be more prone to periodic breathing during sleep, we measured VI and HCVR and monitored ventilatory pattern in seven healthy subjects before and during an infusion of adenosine (80 micrograms.kg-1.min-1) during uninterrupted sleep. Adenosine increased the mean sleeping VI (7.6 +/- 0.4 vs. 6.5 +/- 0.4 l/min, P less than 0.05) and decreased mean end-tidal CO2 values (42.4 +/- 1.2 vs. 43.7 +/- 1.0 Torr, P = 0.06, paired t test) during stable breathing. In six of seven subjects, periodic breathing occurred during this infusion. The amplitude (maximum VI--mean VI) and period length of this periodic breathing was variable among subjects and not predicted by baseline HCVR [correlation coefficients (r) = 0.64, P = 0.17 and r = -0.1, P = 0.9, respectively]. Attempts to measure HCVR during adenosine infusion were unsuccessful because of frequent arousals and continued periodic breathing despite hyperoxic hypercapnia. We conclude that adenosine infusion increases VI and produces periodic breathing during sleep in most normal subjects studied.     

Cardiac changes during arousals from non-REM sleep in healthy volunteers

Our aim was to evaluate cardiac changes evoked by spontaneous and sound-induced arousals from sleep. Cardiac responses to spontaneous and auditory-induced arousals were recorded during overnight sleep studies in 28 young healthy subjects (14 males, 14 females) during non-rapid eye movement sleep. Computerized analysis was applied to assess beat-to-beat changes in heart rate, atrio-ventricular conductance, and ventricular repolarization from 30 s before to 60 s after the auditory tone. During both types of arousals, the most consistent change was the increase in the heart rate (in 62% of spontaneous and in 89% of sound-induced arousals). This was accompanied by an increase or no change in PR interval and by a decrease or no change in QT interval. The magnitude of all cardiac changes was significantly higher for tone-induced vs. spontaneous arousals (mean +/- SD for heart rate: +9 +/- 8 vs. +13 +/- 9 beats per min; for PR prolongation: 14 +/- 16 vs. 24 +/- 22 ms; for QT shortening: -12 +/- 6 vs. -20 +/- 9 ms). The prevalence of transient tachycardia and PR prolongation was also significantly higher for tone-induced vs. spontaneous arousals (tachycardia: 85% vs. 57% of arousals, P < 0.001; PR prolongation: 51% vs. 25% of arousals, P < 0.001). All cardiac responses were short-lasting (10-15 s). We conclude that cardiac pacemaker region, conducting system, and ventricular myocardium may be under independent neural control. Prolongation of atrio-ventricular delay may serve to increase ventricular filling during arousal from sleep. Whether prolonged atrio-ventricular conductance associated with increased sympathetic outflow to the ventricular myocardium contributes to arrhythmogenesis during sudden arousal from sleep remains to be evaluated.     

Decreased fractal component of human heart rate variability during non-REM sleep

The physiological significance of the fractal component of short-term, spontaneous heart rate variability (HRV) in humans remains unclear. The aim of the present study was to gain further information about the respective fractal components by extracting them from HRV, blood pressure variability (BPV), and instantaneous lung volume (ILV) time series via coarse graining spectral analysis in nine healthy subjects during waking and sleep states. The results show that the contribution made by the fractal component to the total variance in the beat-to-beat R-R interval declined significantly as the depth of non-rapid eye movement (non-REM) sleep increased, that the ILV time series was largely periodic (i.e., nonfractal), and that BPV was unaffected by sleep stage. Finally, the fractal component of HRV during REM sleep was found to be quite similar to that seen during waking. These results suggest that mechanisms involving electroencephalographic desynchronization and/or conscious states of the brain are reflected in the fractal component of HRV.     

Pupillary behavior during wakefulness,non-REM sleep,and REM sleep in birds is opposite that of mammals

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Effects of naloxone on breathing movements during hypercapnia in the fetal lamb

To determine whether endogenous opioids influence the fetal breathing response to CO2 we have investigated the effect of the opiate antagonist, naloxone on the incidence, rate, and amplitude of breathing movements during hypercapnia in fetal lambs in utero. In 20 experiments in six pregnant sheep (130-145 days gestation) hypercapnia was induced by giving the ewe 4-6% CO2-18% O2 in N2 to breathe for 60 min. After 30 min of hypercapnia either naloxone (13 experiments) or saline (7 experiments) was infused intravenously for the remaining 30 min. During hypercapnia breath amplitude increased from 5.8 +/- 0.5 to 9.1 +/- 1.2 mmHg (P less than 0.001), and infusion of naloxone was associated with a further significant increase to 15.7 +/- 1.2 mmHg (P less than 0.001). Naloxone had no effect on the incidence or rate of breathing movements during hypercapnia. After hypercapnia there was a significant decrease in the incidence of fetal breathing movements in the naloxone group (14.7 +/- 3.2%). Infusion of saline during hypercapnia had no effect on incidence, rate, or amplitude of fetal breathing movements. These results suggest that endogenous opioids act to suppress or limit breath amplitude during hypercapnia but do not affect rate or incidence of breathing movements.     

The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors.

The relative importance of peripheral vs. central chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with intact carotid bodies. We studied three unanesthetized dogs during normal sleep in a preparation in which intact carotid body chemoreceptors could be reversibly isolated from the systemic circulation and perfused. Apneic thresholds and the CO(2) reserve (end-tidal Pco(2) eupneic - end-tidal Pco(2) apneic threshold) were determined using a pressure support ventilation technique. Dogs were studied when both central and peripheral chemoreceptors sensed transient hypocapnia induced by the pressure support ventilation and again with carotid body isolation such that only the central chemoreceptors sensed the hypocapnia. We observed that the CO(2) reserve was congruent with4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal Pco(2), 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155-164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep.     

Influence of testosterone on breathing during sleep

Apneas and hypopneas during sleep occur more frequently in men than women. Disordered breathing is also reported to increase in hypogonadal men following testosterone administration. This suggests a hormonal influence on sleeping respiratory pattern. We therefore studied respiratory rhythm during sleep in 11 hypogonadal males both on and off testosterone-replacement therapy. In four subjects the anatomy (computerized tomography) and airflow resistance of the upper airway were also determined on both occasions. Sleep stage distribution and duration were unchanged following androgen administration. However, both apneas and hypopneas increased significantly during testosterone replacement so that the total number of disordered breathing events (apneas + hypopneas) per hour of sleep rose from 6.4 +/- 2.1 to 15.4 +/- 7.0 (P less than 0.05). This was a highly variable event with some subjects demonstrating large increases in apneas and hypopneas when androgen was replaced, whereas others had little change in respiration during sleep. Upper airway dimensions, on the other hand, were unaffected by testosterone. These results suggest that testosterone contributes to sleep-disordered breathing through mechanisms independent of anatomic changes in the upper airway.     

Dynamics of breathing in the hypoxic awake lamb

Newborn mammals respond to hypoxia with an immediate hyperventilation that is rapidly dampened. Changes in mechanical properties of the respiratory system during hypoxia have been considered an important reason for this fall in minute ventilation (VE). We have studied the dynamic mechanical behavior of the respiratory system in eight unanesthetized intact newborn lambs (mean age 2 days) during normoxia and hypoxia (FIO2 = 0.08). Mouth pressure (P), airflow (V), and volume (V) were recorded while lambs were breathing through a leak-proof face mask and a pneumotachograph. Active compliance (C') and resistance (R') of the respiratory system were computed from P developed during an inspiratory effort against airway closure at end expiration and V and V of the preceding breaths. Tidal expiratory V-V curves were analyzed to estimate the elevation in functional residual capacity (FRC) over resting volume (Vr). After hypoxia, there was an immediate increase in VE in the first 2 min, from 0.49 to 1.13 l.kg-1.min-1, followed by a rapid decrease to 0.80. After 8 min of hypoxia, C' was unchanged. The inspiratory R' decreased during hypoxia, probably reflecting a drop in inspiratory laryngeal resistance. The expiratory V-V curves during hypoxia showed considerable braking, often with a double peak in expiratory V. This pattern was only occasionally seen during normoxia. In animals with a linear segment of the expiratory V-V curves the FRC-Vr difference could be calculated and averaged 1.93 ml/kg during normoxia and 3.47 during hypoxia. The recoil P of the respiratory system at end expiration was 0.75 cmH2O during normoxia vs. 1.63 cmH2O during hypoxia (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible mechanisms of periodic breathing during sleep

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.     

Characterization of pharyngeal resistance during sleep in a spectrum of sleep-disordered breathing.

Aims of the study were 1) to compare Hudgel's hyperbolic with Rohrer's polynomial model in describing the pressure-flow relationship, 2) to use this pressure-flow relationship to describe these resistances and to evaluate the effects of sleep stages on pharyngeal resistances, and 3) to compare these resistances to the pressure-to-flow ratio (DeltaP/V). We studied 12 patients: three with upper airway resistance syndrome (UARS), four with obstructive sleep hypopnea syndrome (OSHS), three with obstructive sleep apnea syndrome (OSAS), and two with simple snoring (SS). Transpharyngeal pressures were calculated between choanae and epiglottis. Flow was measured by use of a pneumotachometer. The pressure-flow relationship was established by using nonlinear regression and was appreciated by the Pearson's square (r(2)). Mean resistance at peak pressure (Rmax) was calculated according to the hyperbolic model during stable respiration. In 78% of the cases, the value of r(2) was greater when the hyperbolic model was used. We demonstrated that Rmax was in excellent agreement with P/V. UARS patients exhibited higher awake mean Rmax than normal subjects and other subgroups and a larger increase from wakefulness to slow-wave sleep than subjects with OSAS, OSHS, and SS. Analysis of breath-by-breath changes in Rmax was also a sensitive method to detect episodes of high resistance during sleep.     

Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits

Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10-23 postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.     

Relationship of ethanol blood level to REM and non-REM sleep time and distribution in the rat.

Direct electroencephalographic (EEG) and integrated electromyographic (EMG) recordings were analyzed for possible changes in the REM and non-REM sleep time in chronically implanted rats given 0, 1, 2, and 4 g/kg ethanol. REM and non-REM sleep were found, respectively, to be lessened and elevated in a dose-related manner. The degree of disruption of normal sleep-awake patterns was also found to correspond with blood-ethanol concentrations for the different doses of ethanol. These findings are discussed in relation to the influence of ethanol on the sleep of the human subject and the suggestion that the rat with chronic EEG and EMG electrodes may serve as a model for studying the degree of disruption of sleep upon chronic exposure to ethanol.