New acoustic method for detecting upper airway obstruction in patients with sleep apnoea.

UNLABELLED: This article investigates a new acoustic device to assess the behaviour of the upper airway in patients with OSA. Currently there is no simple non-invasive method to perform such measurements. As such this paper describes the device in probing the patency of the airway during sleep and increasing the efficiency of diagnosing OSA. BACKGROUND AND OBJECTIVE: OSA is a common disorder resulting in health and economic burdens. Currently identifying OSA in patients involves expensive techniques that require overnight studies in a laboratory setting with qualified staff. This paper tests a new acoustic device (AirwayClear (AC)) for assessing upper airway patency in human subjects with OSA. We hypothesize that obstructive apnoeas would be detected equally well with AC and polysomnography (PSG). METHODS: Twenty-three patients with severe OSA underwent an overnight CPAP titration study. We introduced pseudorandom noise (600-1200 Hz) using AC to the patient's nasal mask during 1 h of subtherapeutic CPAP. AC determined a measure of airway patency based on the level of pseudorandom noise reaching a sternal notch sensor. The ability of AC to detect obstructive respiratory events was compared with standard PSG. RESULTS: Three hundred and twenty-two obstructive events (obstructive and mixed apnoeas) were identified by PSG. AC scored 80% as complete obstructions and 16% as partial obstructions. Conversely, AC detected 281 complete obstructions. PSG recognized 84% as apnoeas and scored 11% as hypopnoeas. Of the 204 hypopnoeas identified with PSG, AC indicated the airway was partially or completely obstructed in 69% of patients. A Bland-Altman analysis for the apnoeas from the two measures showed a mean difference of 2.3 events/h and 95% confidence intervals of +/-15.5 events/h. CONCLUSIONS: We conclude that AC is able to track airway patency and to identify airway closure in patients with OSA.

In utero model for pharmacologically investigating spontaneous activity during early ontogeny.

We describe an in utero model in which it is possible to investigate the involvement of supraspinal and spinal neurons in the genesis of spontaneous motor activity, a feature of early fetal life. To date almost all studies of the circuits that give rise to spontaneous motor activity during early ontogeny, and the neurotransmitters involved, have been carried out with in vitro models. Limitations of in vitro models include the relatively short viability of the preparation and the need to stimulate the nervous system either pharmacologically or electrically to produce the activity to be studied, in contrast to the activity that spontaneously occurs normally in utero. Our model uses fetal sheep, chronically instrumented with electromyogram electrodes and a catheter placed either intrathecally at the spinal level or in the peritoneal cavity. Motor activity can be studied over lengthy periods of fetal life and it is possible to examine the effects of infusing agonists and antagonists of central neurotransmitters on spontaneous motor activity. The use of our new model in parallel with the pre-existing in vitro models has the potential to add substantially to our understanding of the mechanisms behind changes in spontaneous activity that occur throughout fetal life.

Increased peripheral chemosensitivity via dopaminergic manipulation promotes respiratory instability in lambs.

Periodic breathing (PB) is an instability of the respiratory control system believed to be mediated principally by the peripheral chemoreceptors. We hypothesised that domperidone, a dopamine D(2)-receptor antagonist that increases carotid body sensitivity to O(2) and CO(2), would promote PB through an increase in the loop gain (LG) of the respiratory control system. Domperidone significantly increased controller gain for oxygen (p<0.05) and gave rise, following post-hyperventilation apnea, to an increased incidence of PB (14% vs. 86%), an increased PB epoch duration, and a decrease in duty ratio of PB (p<0.001); these changes are consistent with domperidone increasing LG. Although domperidone increased controller gain for CO(2) (p<0.05), the contribution of Pa(CO)(2) oscillations to the genesis of PB in the lamb remained small. We conclude that domperidone increases LG in the lamb via an increase in controller gain for oxygen. Our study demonstrates that a quantitative understanding of the factors that determine LG provides insight into the cause of PB.

The development of descending projections from the brainstem to the spinal cord in the fetal sheep.

BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSION: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord.

A map of the major nuclei of the fetal sheep brainstem.

The fetal sheep has been used to investigate a wide range of developmental and pathological processes such as the effect of severe hypoxia, asphyxia, or intrauterine infection on the brain but, until now, there has been no complete description of the normal anatomical organisation of neuronal groups to facilitate interpretation of these studies. In this paper, we describe the major nuclei of the fetal sheep brainstem based on a study of 5 fetal sheep at 140 days of gestation (G140: term is G147). Nuclei were identified with the aid of brain atlases available for other species, and from the previously published, partial descriptions available for the sheep. Fifty-five distinct nuclei were identified after Nissl (thionin) staining, and their caudal and rostral margins were defined. This paper provides an easy reference to the position of the major nuclei within the fetal sheep brainstem, and can be used as a guide for future studies examining the organisation of neuronal populations under normal and pathological conditions in this animal model.

Expulsion of liquid from the fetal lung during labour in sheep.

Effective gas exchange after birth requires clearance of most of the liquid filling the lung during gestation. To date the focus has been on active Na(+) transport from lung lumen to interstitium, but Na(+) transport begins only close to delivery, making it an unlikely mechanism for clearing the bulk of fetal lung liquid. We hypothesised that fetal trunk muscle contractions, known to occur in labour, are involved in lung liquid clearance. We measured maternal uterine contractions, fetal tracheal flow directly and fetal electromyograms in thoracic and abdominal muscles. During labour in five fetal sheep, brief flow pulses were observed in the trachea, most of which expelled a small volume of lung liquid. Tracheal flow pulses were associated with fetal muscle contractions 89% of the time, which were associated on 91% of occasions with uterine contractions. Our results suggest that liquid contained in the fetal lung is cleared before and during labour as a result of fetal muscular effort, perhaps stimulated by uterine contractions.

Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep.

We studied the impact of endotoxemia on cerebral blood flow (CBF), cerebral vascular resistance (CVR), and cerebral oxygen transport (O(2) transport) in fetal sheep. We hypothesized that endotoxemia impairs CBF regulation and O(2) transport, exposing the brain to hypoxic-ischemic injury. Responses to lipopolysaccharide (LPS; 1 microg/kg iv on 3 consecutive days, n = 9) or normal saline (n = 5) were studied. Of LPS-treated fetuses, five survived and four died; in surviving fetuses, transient cerebral vasoconstriction at 0.5 h (DeltaCVR approximately +50%) was followed by vasodilatation maximal at 5-6 h (DeltaCVR approximately -50%) when CBF had increased (approximately +60%) despite reduced ABP (approximately -20%). Decreased CVR and increased CBF persisted 24 h post-LPS and the two subsequent LPS infusions. Cerebral O(2) transport was sustained, although arterial O(2) saturation was reduced (P < 0.05). Histological evidence of neuronal injury was found in all surviving LPS-treated fetuses; one experienced grade IV intracranial hemorrhage. Bradykinin-induced cerebral vasodilatation (DeltaCVR approximately -20%, P < 0.05) was abolished after LPS. Fetuses that died post-LPS (n = 4) differed from survivors in three respects: CVR did not fall, CBF did not rise, and O(2) transport fell progressively. In conclusion, endotoxin disrupts the cerebral circulation in two phases: 1) acute vasoconstriction (1 h) and 2) prolonged vasodilatation despite impaired endothelial dilatation (24 h). In surviving fetuses, LPS causes brain injury despite cerebral O(2) transport being maintained by elevated cerebral perfusion; thus sustained O(2) transport does not prevent brain injury in endotoxemia. In contrast, cerebral hypoperfusion and reduced O(2) transport occur in fetuses destined to die, emphasizing the importance of sustaining O(2) transport for survival.

Maturation of respiratory control and the propensity for breathing instability in a sheep model.

Limited evidence suggests that the ventilatory interaction between O(2) and CO(2) is additive after birth and becomes multiplicative with postnatal development. Such a switch may be linked to the propensity for periodic breathing (PB) in infancy. To test this idea, we characterized the maturation of the respiratory controller and its effect on breathing stability in approximately 10-day-old lambs and 6-mo-old sheep. We measured 1) carotid body sensitivity via dynamic ventilatory responses to step changes in O(2) and CO(2), 2) steady-state ventilatory sensitivity to CO(2) under hypoxic and hyperoxic conditions, 3) the dependence of the apneic threshold on arterial Po(2), and 4) the effect of hypoxic or hypercapnic gas inhalation during induced PB. Stability of the system was assessed using surrogate measures of loop gain. Peripheral sensitivity to O(2) was higher in newborn than in older animals (P < 0.05), but peripheral CO(2) sensitivity was unchanged. Central CO(2) sensitivity was reduced with age, but the slopes of the ventilatory responses to CO(2) were the same in hypoxia and hyperoxia. Reduced arterial Po(2) caused a leftward shift in the apneic threshold at both ages. Inspiration of hypoxic gas during PB immediately halted PB, whereas hypercapnia stopped PB only after one or two further PB cycles. We conclude that the controller in the sheep remains additive over the first 6 mo of life. Our results also show that the loop gain of the respiratory control system is reduced with age, possibly as a result of a reduction of peripheral O(2) sensitivity.