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Objectives: Current clinical hyperpolarized He lung ventilation MR imaging protocols rely on the patient's ability to control inhalation and exhalation and hold their breath on demand. This is impractical for intensive care unit patients under ventilation or for pediatric populations under the age of 3 to 4 years. To address this problem, we propose a free-breathing protocol for hyperpolarized He lung ventilation spiral imaging. This approach was evaluated in vitro and on rabbits., Materials and Methods: The protocol was implemented on a clinical 1.5-T magnetic resonance imaging scanner. Ventilation images were acquired using a spiral sequence, in vitro on a lung phantom and in vivo on rabbits, the animal breathing freely from a gas reservoir. Dynamic spiral ventilation images were reconstructed using retrospective Cine synchronization. Magnetic resonance (MR) signal dynamics was modeled taking account of gas inflow and outflow, radiofrequency depolarization and oxygen-induced relaxation., Results: Cine ventilation images acquired in spontaneously breathing rabbits were reconstructed with a temporal resolution of 50 milliseconds. Gas volume variations and time-to-maximum maps were obtained. The numerical model was validated in vitro and in vivo with various gas mixtures. Ventilation parameters (functional residual capacity, tidal volume, and alveolar pO2) were extracted from the MR signal dynamics., Conclusions: Ventilation imaging can be performed at tidal volume using a simple experimental protocol, without any ventilation device or breath-hold period. Acquisition time, SNR and pO2 decay can be optimized using the developed numerical model. Free-breathing ventilation images can be obtained without artifacts related to motion or gas flow. Lastly, parametric maps can be derived from the time-resolved ventilation images and physiological parameters extracted from the global signal dynamics.

A non-invasive and free-breathing hyperpolarized (HP) (3)He imaging protocol for small animals was implemented and validated on rats for lung function imaging. Animals were allowed to breathe a mixture of air and (3)He from a mask and a gas reservoir fitted to their heads. Radial imaging sequences were used, and MRI signal intensity changes were monitored for retrospective cine image reconstruction. The ventilation cycle of the animals was imaged with a 100 ms temporal resolution. The sliding window imaging technique was applied to reconstruct 5 ms time-shifted image series covering the complete breathing cycle. Image series were processed to extract quantitative ventilation parameters such as the gas arrival time. The reproducibility and the non-invasiveness of this ventilation imaging protocol were evaluated by multiple acquisitions on the same animals., (c 2006 John Wiley & Sons, Ltd.)

We recently reported that glottic closure was present throughout central apneas in awake lambs. The present study tested whether glottic closure was also observed during periodic breathing (PB). We attempted to induce PB in 21 nonsedated lambs on return from hypocapnic hypoxia to room air. Airflow and thyroarytenoid (a laryngeal constrictor, n = 16), cricothyroid (a laryngeal dilator, n = 10), and abdominal (n = 9) muscle electrical activity (EMG) were monitored continuously. PB was observed in 16 lambs, with apneic phases in 8 lambs. Thyroarytenoid muscle EMG was observed at the nadir of PB, either throughout apnea or with prolonged expiration during the lowest respiratory efforts. Phasic inspiratory cricothyroid muscle EMG and phasic expiratory abdominal EMG disappeared at the nadir of PB. Active glottic closure at the nadir of PB, without abdominal muscle contraction, could be a beneficial mechanism, preserving alveolar gas stores for continuing gas exchange during the apneic/hypopneic phase of PB. However, consequences of active glottic closure on ventilatory instability, either enhancing or reducing, are unknown.

Spontaneous periodic breathing, although a common feature in fullterm and preterm human infants, is scarce in other newborn mammals. The aim of this study was to induce periodic breathing in lambs. Four 10-day-old and two <48-h-old awake lambs were instrumented with jugular catheters connected to an extracorporeal membrane lung aimed at controlling arterial PCO2 (PaCO2). Arterial PO2 (PaO2) was set and maintained at the desired level by changing inspired O2 fraction and providing O2 through a small catheter into the "apneic" lung. At a critical PaO2/PaCO2 combination, the four 10-day-old lambs exhibited periodic breathing that could be initiated, terminated, and reinitiated on demand. In the 2-day-old lambs with low chemoreceptor gain, periodic breathing was hardly seen, regardless of the trials done to find the critical PO2/PCO2 combination. We conclude that periodic breathing can be induced in lambs and depends on critical PaO2/PaCO2 combinations and maturity of the chemoreceptors.

Although studies on lambs have shown that carotid body sensitivity to O2 is reset postnatally, it is still unknown whether O2 and CO2 peripheral chemoreflexes undergo parallel postnatal maturation. The present study was designed to analyze maturation of O2 and CO2 peripheral chemoreflexes in 10 lambs at < 24 h and at 12 days of age. We measured the ventilatory (VE) response to three tidal breaths of pure N2 or 13% CO2 in air. Overall, the N2 peripheral chemoreflex increased significantly with maturation [VE/end-tidal O2 (ml.min-1.kg-1.Torr-1) = 2.94 +/- 0.91 at < 24 h vs. 5.13 +/- 0.59 at 12 days, P < 0.05], whereas the CO2 peripheral chemoreflex did not change (VE/end-tidal CO2 = 7.04 +/- 0.98 at < 24 h vs. 7.75 +/- 1.07 at 12 days, not significant). We conclude that the CO2 peripheral chemoreflex does not change in awake lambs within the time frame studied, in contrast to a marked postnatal maturation of the O2 peripheral chemoreflex. The different time courses of O2 and CO2 peripheral chemoreflex maturation support the concept that carotid body sensitivities to O2 and CO2 do not depend on the same basic mechanisms.

This study was designed to determine the effect of the removal of chemical stimuli on breathing rhythmicity in awake newborn lambs; it was also designed to define the chemical threshold below which breathing would stop [arterial PCO2 (PaCO2) apnea threshold]. We used a technique of graded extracorporeal CO2 removal with apneic oxygenation in three groups of animals according to age and carotid body (CB) integrity: < 2 days, CB intact (n = 5); 12 days, CB intact (n = 7); and 12 days, CB denervated (CBD; n = 5). In all animals, whatever their age and CB status, suppression of the chemical drive resulted in sustained apnea. The study, performed at four constant levels of oxygenation (hyperoxia, normoxia, moderate hypoxia, and severe hypoxia), allowed precise determination of the PaCO2 apnea threshold. We found that this PaCO2 apnea threshold depended on the degree of postnatal maturation (it was higher in the younger lambs), the level of arterial oxygenation (it was lowered by hypoxia), and CB status (it was higher in CBD animals). Moreover, we found that the 12-day-old CBD lambs breathe at a level of PaCO2 set close to the point of apnea.(ABSTRACT TRUNCATED AT 250 WORDS)

In awake lambs we investigated the role of the peripheral chemoreceptors in producing dynamic ventilatory (VE) responses to CO2. The immediate VE response, within 15 s, to transient CO2 inhalation was studied in two groups: 1) five lambs before carotid denervation and 2) the same lambs after carotid denervation. The time course of VE responses during the first 60 s after a step change to 8% inspired CO2 was also studied in lambs after carotid denervation and in a group of six carotid body-intact lambs 10-11 days of age. Acute CO2 responses were assessed using step changes to various concentrations of CO2 + air and CO2 + O2, while VE was recorded breath by breath. Intact lambs exhibited a brisk VE response to step changes in CO2, beginning after 3-5 s. Hyperoxia altered but did not suppress the dynamic VE CO2 response when the carotid chemoreceptors were intact. Carotid denervation markedly reduced the VE response during the first 25 s after a CO2 step change, revealing the time delay required for the central chemoreceptors to produce an effective VE response. The residual VE response remaining after CD was thought to be mediated by the remaining aortic body chemoreceptors and was eliminated by adding O2 to the CO2 challenges. However, after carotid denervation, even with CO2 + hyperoxia, the onset of a small tidal volume response was apparent by 10-12 s.(ABSTRACT TRUNCATED AT 250 WORDS)

We aimed to investigate the role of the carotid bodies in the ventilatory response to keto-doxapram, and whether this response was dose-dependent; we studied two group (n = 5 per group) of awake, intact and carotid-body denervated (CBD) lambs, aged 10-15 days. At 20 min intervals, they received 0.5, 1.0, 2.5 and 5.0 m g/kg mg/kg of keto-doxapram as an intravenous bolus infusion. Plasma keto-doxapram was measured (HPLC). Ventilation was recorded via a face mask and a pneumotachograph. In intact lambs, an immediate dose-dependent increase in minute ventilation (V1) was observed. At 2 min, VI increased from baseline by 125 +/- 28, 212 +/- 49, 378 +/- 41 and 637 +/- 92 mol.kg 1.min 1 (mean +/- SE, P less than 0.01) corresponding to the foregoing incremental doses. A significant correlation was observed between the peak VI and the corresponding plasma keto-doxapram concentrations (r = 0.73, P less than 0.0003). In CBD lambs, VI increased significantly less than in intact animals. In conclusion, early ventilatory response to keto-doxapram depends mainly on intact carotid bodies, and the effect is dose-dependent.

It is generally accepted that hypoxia in early life results in active laryngeal braking of expiratory airflow via the recruitment of glottic adductor muscles. We examined the electromyogram expiratory activity of the thyroarytenoid muscle in seven 11- to 18-day-old awake nonsedated lambs exposed to an inspired O2 fraction of 0.08 for 18 min. The lambs breathed through a face mask and a pneumotachograph. During baseline prehypoxic breathing, the thyroarytenoid muscle was largely inactive in each awake lamb. Unexpectedly, no recruitment of the thyroarytenoid muscle was recorded during hypoxia in any of the seven lambs; simultaneous examination of the flow-volume curves revealed an absence of expiratory airflow braking. Also unexpectedly, marked expiratory activity of the thyroarytenoid muscle was recorded, with each expiration occurring within less than 10 s after the return to room air. The resulting delay of expiration was apparent in the flow-volume loops. Thus, in awake 11- to 18-day-old lambs, 1) active expiratory glottic adduction is absent during hypoxia and 2) a return from hypoxia to room air results in prolonged expiration as well as active glottic adduction that controls end-expiratory lung volume.

This study was designed to elucidate the effect of hypoxia on the breathing rhythmicity and the effect of hypoxia on periodic breathing (PB) in two groups of newborn lambs (less than 2 days and 10 days of age). Lambs undergoing a hypoxic ventilatory test [0.08 inspired O2 fraction (FIo2) for 13 min] experienced no apnea or PB in hypoxia, but all developed PB during the 1-min period immediately after their abrupt return to 0.21 FIo2. This PB occurred when alternation of arterial PO2 and PCO2 in mild hypoxic and hypocapnic conditions induced an overshoot-undershoot response of the chemical drive to breathe. The magnitude of PB was found to be greater in the animals with a higher peripheral chemoreflex sensitivity to hypoxia but ceased altogether when the hypoxic-hypocapnic conditions were resolved. When these conditions were removed more quickly, that is, when the animals were returned either to 0.50 FIo2 or to 0.03 FIco2, no PB was observed. To clarify the role of hypoxia as a central depressant on the genesis of PB, we tested to determine whether additional central tissue hypoxia, using carboxyhemoglobin (30%), would worsen the episodes of PB. No effect on breathing rhythmicity was observed. These findings suggest not only that, in newborn animals and adults, the mechanisms of post-hypoxia-induced PB are identical but that the PB elicited in mild hypoxic conditions is a peripheral chemoreflex-mediated event rather than a centrally mediated one.

This study was undertaken to measure the neonate's response to CO-induced hypoxia in the first 10 days of life. CO breathing was used to induce hypoxia because CO causes tissue hypoxia with no or minimal chemoreceptor stimulation. An inspired gas mixture of 0.25 to 0.5% CO in air was used to raise the blood carboxyhemoglobin (HbCO) progressively from 0 to 60% over approximately 20 min. The study, conducted in awake conscious lambs aged 2 and 10 days, consisted in measuring the response of ventilation and the change in arterial blood gases during the rise of HbCO. The results showed that the 2- and 10-day-old lambs tolerated very high HbCO levels without an increase in minute ventilation (VE) and without metabolic acidosis. At both ages, HbCO caused no VE change until HbCO levels rose to between 45 and 50% after which the VE change was exponential in some animals but minimal in others. The VE change was brought about by a rise in tidal volume and respiratory frequency. During the period of maturation from 2 to 10 days, there was a small shift to the right in the VE-HbCO response. In the 10-day-old lambs the VE response to high HbCO was greater than that of the 2-day-olds because of the lambs' higher respiratory frequency response. Six of the 10-day-old lambs but only two of the 2-day-old lambs showed a hypoxic tachypnea to HbCO of 55-65%. None of the lambs developed periodic breathing, dysrhythmic breathing, or recurrent apneas with an HbCO level as high as 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to determine the effects of sleep deprivation on respiratory events during sleep in healthy infants. Ten unsedated full-term infants (1-6 mo) were monitored polygraphically during "afternoon naps" on a control day and on the day after sleep deprivation. Respiratory events, i.e., central apnea, obstructive apnea and hypopnea, and periodic breathing were tabulated. Results for respiratory events were expressed as 1) indexes of the total number of respiratory events and of specific respiratory events per hour of total sleep (TST), "quiet" sleep (QS) and "active" sleep (AS) times; 2) total duration of total and specific respiratory events, expressed as a percentage of TST, QS, and AS times. After sleep deprivation, significant increases were observed for 1) respiratory event (P less than 0.001), central apnea (P less than 0.05), and obstructive respiratory event (P less than 0.01) indexes; 2) respiratory event time as a percentage of TST (P less than 0.002) and as a percentage of AS time (P less than 0.001); 3) obstructive respiratory event time as a percentage of TST (P less than 0.01), QS (P less than 0.05), and AS times (P less than 0.002). The present study shows that short-term sleep deprivation in healthy infants increases the number and timing of respiratory events, especially obstructive events in AS.

In neonates, rib cage motion on inspiration during rapid eye movement sleep is almost exclusively paradoxical. We wondered whether or not duration of paradoxical inward rib cage motion on inspiration during rapid eye movement sleep decreases in infancy and early childhood. Thirteen healthy infants from 7 to 31 months of age were tested during natural afternoon naps. Electroencephalogram, electrooculogram and electromyogram were all recorded. Airflow was measured by nasal and buccal thermistors, abdominal and rib cage anteroposterior diameters by magnetometers. Transcutaneous partial pressure of O2 was monitored. Diaphragmatic electromyographic activity was recorded using surface electrodes. The average total sleep time was 138 min ranging from 107 to 186 and rapid eye movement sleep time amounted to 15% of total sleep time ranging from 6 to 25. During rapid eye movement sleep, the total duration of paradoxical inward rib cage motion was measured and expressed as a percentage of rapid eye movement sleep time. We found that duration of paradoxical inward rib cage motion during rapid eye movement sleep decreased significantly with age (r = -0.66, P less than 0.02) which may be explained by the changes in chest wall compliance and geometry of the rib cage occurring with growth. We observed no decrease in transcutaneous partial pressure in O2 during paradoxical inward rib cage motion during rapid eye movement sleep in infants in contrast to that reported in neonates.