[show abstract][hide abstract] ABSTRACT: Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O2. Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL-1α and IL-1β on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1α/β in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.
Proceedings of the National Academy of Sciences 08/2013; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1).
To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2π/(2πDR - sin2πDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB.
After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB.
In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients.
Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy.
American Journal of Respiratory and Critical Care Medicine 08/2011; 184(9):1067-75. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Brief recurrent apneas in preterm infants and adults can precipitate rapid and severe arterial O(2) desaturation for reasons that remain unclear.
We tested a mathematically derived hypothesis that when breathing terminates apnea, mixed-venous hypoxemia continues into the subsequent apnea; as a result, there is a surge in pulmonary O(2) uptake that rapidly depletes the finite alveolar O(2) store, thereby accelerating arterial O(2) desaturation.
Recurrent apneas were simulated in an experimental lamb model. Pulmonary O(2) uptake was calculated from continuously measured arterial and mixed-venous O(2) saturation and cardiac output.
Direct measurements revealed that asynchrony in the desaturation and resaturation of arterial and venous blood gave rise to dips and surges in O(2) uptake. After desaturation to 50%, a typical nadir in preterm infants, O(2) uptake surged to a peak of 176.9 ± 7.8% of metabolic rate. During subsequent apneas, desaturation rate was increased two- to threefold greater than during isolated apneas, in direct proportion to the magnitude of the surge in O(2) uptake (P < 0.001; R(2) = 0.897). Application of our mathematical model to a published recording of cyclic apneas in a preterm infant precisely reproduced the accelerated desaturation rates of up to 15% · s(-1) observed clinically.
Rapid depletion of alveolar O(2) stores by surges in O(2) uptake almost completely explains the acceleration of desaturation that occurs during recurrent apnea. This powerful mechanism is likely to explain the severity of intermittent hypoxemia that is associated with neurocognitive and cardiovascular morbidities in preterm infants and adults.
American Journal of Respiratory and Critical Care Medicine 10/2010; 182(7):961-9. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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).
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.
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.
We conclude that AC is able to track airway patency and to identify airway closure in patients with OSA.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Applied Physiology 09/2009; 107(5):1463-71. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Continous positive airway pressure (CPAP) is used to treat infant respiratory distress syndrome and apnea of prematurity, but its mode of action is not fully understood. We hypothesised that CPAP increases lung volume and stabilises respiratory control by decreasing loop gain (LG). Experimentally induced periodic breathing (PB) in the lamb was terminated early by CPAP in a dose-dependent manner, with a control epoch of 45.4+/-5.1s at zero CPAP falling to 32.9+/-5.4, 13.2+/-4.2 and 9.8+/-3.1s at 2.5, 5 and 10 cmH(2)O, respectively (p<0.001); corresponding duty ratios (duration of the ventilatory phase of PB divided by its cycle duration) increased from 0.50+/-0.02 to 0.62+/-0.05, 0.76+/-0.06 and 0.68+/-0.08, respectively (p<0.001). Since epoch duration and duty ratio are surrogate measures of LG, we conclude that CPAP ameliorates the effects of recurrent central apneas, and perhaps mixed and obstructive apneas, by decreasing LG via increases in lung volume.
[show abstract][hide abstract] ABSTRACT: We describe a novel technique for direct measurement of the unloaded driving-point mechanical mobility of a structure. The method uses an electrically-excited inertial motor/actuator attached directly to the structure under test (SUT) to induce sinusoidal motion in the frequency range 7.5–750 Hz. Two accelerometers, one attached to the actuator frame and the other to the vibrating actuator mass, separately measure the induced motion of the SUT and the vibrating mass. We develop an expression for the driving-point mobility of the SUT using these two measurements and show analytically that any mass-loading effect of the actuator on the measured mobility can be removed mathematically so that the unloaded mobility of the SUT can be determined. In this study we validate the method using a cantilever as a mobility standard. Measured mobility, mode shape and resonant frequency of cantilevers with various lengths were consistent with theoretical predictions for an unloaded cantilever. We conclude that the method can be used to conveniently determine the mobility of a range of structures, without the limitations associated with some of the traditional methods of mobility measurement.
Journal of Sound and Vibration 01/2009; · 1.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Previous studies of the maturation of periodic breathing cycle duration (PCD) with postnatal age in infants have yielded conflicting results. PCD is reported to fall in term infants over the first 6 mo postnatally, whereas in preterm infants PCD is reported either not to change or to fall. Contrary to measured values, use of a theoretical respiratory control model predicts PCD should increase with postnatal age. We re-examined this issue in a longitudinal study of 17 term and 22 preterm infants. PCD decreased exponentially from birth in both groups, reaching a plateau between 4 and 6 mo of age. In preterm infants, PCD fell from a mean of 18.3 s to 9.8 s [95% confidence interval (CI) is +/- 3.2 s]. In term infants, PCD fell from 15.4 s to 10.1 s (95% CI is +/- 3.1 s). The higher PCD at birth in preterm infants, and the similar PCD value at 6 mo in the two groups, suggest a more rapid maturation of PCD in preterm infants. This study confirms that PCD declines after birth. The disagreement between our data and theoretical predictions of PCD may point to important differences between the respiratory controller of the infant and adult.
Pediatric Research 10/2007; 62(3):331-6. · 2.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: We measured the velocity and attenuation of audible sound in the isolated lung of the near-term fetal sheep to test the hypothesis that the acoustic properties of the lung provide a measure of the volume of gas it contains. We introduced pseudorandom noise (bandwidth 70 Hz-7 kHz) to one side of the lung and recorded the noise transmitted to the surface immediately opposite, starting with the lung containing only fetal lung liquid and making measurements after stepwise inflation with air until a leak developed. The velocity of sound in the lung fell rapidly from 187 +/- 28.2 to 87 +/- 3.7 m/s as lung density fell from 0.93 +/- 0.01 to 0.75 +/- 0.01 g/ml (lung density = lung weight/gas volume plus lung tissue volume). For technical reasons, no estimate of velocity could be made before the first air injection. Thereafter, as lung density fell to 0.35 +/- 0.01 g/ml, there was a further decline in velocity to 69.6 +/- 4.6 m/s. High-frequency sound was attenuated as lung density decreased from 1.0 to 0.5 g/ml, with little change thereafter down to a density of 0.35 +/- 0.01 g/ml. We conclude that both the velocity of audible sound through the lung and the degree to which high-frequency sound is attenuated in the lung provide information on the degree of inflation of the isolated fetal lung, particularly at high lung densities. If studies of sound transmission through the lung in the intact organism were to confirm these findings, the acoustic properties of the lung could provide a means for monitoring lung aeration during mechanical ventilation of newborn infants.
Journal of Applied Physiology 07/2005; 98(6):2235-41. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined the effect of hypoxia and hypercapnia administered during deliberately induced periodic breathing (PB) in seven lambs following posthyperventilation apnea. Based on our theoretical analysis, the sensitivity or loop gain (LG) of the respiratory control system of the lamb is directly proportional to the difference between alveolar PO2 and inspired PO2. This analysis indicates that during PB, when by necessity LG is >1, replacement of the inspired gas with one of reduced PO2 lowers LG; if we made inspired PO2 approximate alveolar PO2, we predict that LG would be approximately zero and breathing would promptly stabilize. In six lambs, we switched the inspired gas from an inspiratory oxygen fraction of 0.4 to one of 0.12 during an epoch of PB; PB was immediately suppressed, supporting the view that the peripheral chemoreceptors play a pivotal role in the genesis and control of unstable breathing in the lamb. In the six lambs in which we administered hypercapnic gas during PB, breathing instability was also suppressed, but only after a considerable time lag, indicating the CO2 effect is likely to have been mediated through the central chemoreceptors. When we simulated both interventions in a published model of the adult respiratory controller, PB was immediately suppressed by CO2 inhalation and exacerbated by inhalation of hypoxic gas. These fundamentally different responses in lambs and adult humans demonstrate that PB has differing underlying mechanisms in the two species.
Journal of Applied Physiology 03/2005; 98(2):437-46. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although the lungs and pericardium constrain the heart and limit cardiac output, no method exists to assess this constraint in sick newborns. We hypothesize that a useful estimate of ventricular constraint may be obtained by measuring right atrial pressure (P(RA)) in the newborn. To test this hypothesis, we measured P(RA), thoracic inferior vena caval pressure (P(IVC); saline-filled catheters), and ventricular constraint (pericardial pressure, P(PER); liquid-containing balloon) in 4-wk-old (neonatal, n = 12) and 3-day-old (newborn, n = 6) anesthetized lambs. The measurements were made while LV filling pressure was altered (0-20 mmHg) and while positive end-expiratory pressure (PEEP) was maintained at 2.5 or 15 cmH2O. In all of the lambs, a strong linear relationship (r) existed between P(RA) and P(PER) (P(RA) = 1.19 P(PER) + 0.0, r = 0.99) and between P(IVC) and P(PER) (P(IVC) = 1.24 P(PER) + 0.1, r = 0.99; PEEP of 2.5 cmH2O). Similar relationships were also observed with increased PEEP (P(RA) = 1.29 P(PER)-1.2, r = 0.98 and P(IVC) = 1.32 P(PER)-1.2, r = 0.97). Because P(RA) provides an accurate measure of ventricular constraint in the normal lamb, it may be a useful measure of ventricular constraint in the sick newborn.
[show abstract][hide abstract] ABSTRACT: High inspired oxygen concentrations have recently been recommended to control Cheyne-Stokes respiration in adults, with the intention of averting periodic apnea and its attendant arterial desaturation. We report a case study on an infant presenting with recurrent apnea and cyanosis in which oxygen treatment led to a gross form of respiratory instability we call episodic breathing, in which a breathing phase of 60 to 90 s alternated with an apnea lasting up to 60 s. When oxygen was discontinued, a profound arterial desaturation developed before breathing recommenced and restored oxygen levels. We propose that episodic breathing is an unusual respiratory pattern that involves the central chemoreceptors and results from the ventilatory threshold (the central PCO(2) at which breathing starts) lying considerably above the apneic threshold (the central PCO(2 )at which breathing stops). This feature predisposes to lengthy periods of hyperpnea alternating with lengthy periods of apnea. We suggest that when the case infant returned to air during episodic breathing, termination of apnea was entirely dependent upon carotid body activity, which reached a sufficient level to restart breathing only when arterial desaturation was severe. We conclude that oxygen therapy involves potential risks when employed to treat respiratory disorders involving unstable breathing patterns in the infant.
American Journal of Respiratory and Critical Care Medicine 07/2000; 161(6):2107-11. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: A midsystolic plateau differentiates the pattern of fetal pulmonary trunk blood flow from aortic flow. To determine whether this plateau arises from interactions between the left (LV) and right ventricle (RV) via the ductus arteriosus or from interactions between the RV and the lung vasculature, we measured blood flows and pressures in the pulmonary trunk and aorta of eight anesthetized (ketamine and alpha-chloralose) fetal lambs. Wave-intensity analysis revealed waves of energy traveling forward, away from the LV and the RV early in systole. During midsystole, a wave of energy traveling back toward the RV decreased blood flow velocity from the RV and produced the plateau in blood flow. Calculations revealed that this backward-traveling wave originated as a forward-traveling wave generated by the RV that was reflected from the lung vasculature back toward the heart and not as a forward-traveling wave generated by the LV that crossed the ductus arteriosus. Elimination of this backward-traveling wave and its associated effect on RV flow may be an important component of the increase in RV output that accompanies birth.
Journal of Applied Physiology 12/1999; 87(5):1637-43. · 3.48 Impact Factor