Fractal dimension of pulmonary gas and blood distribution assessed by synchrotron K-edge subtraction imaging: effect of bronchoconstriction.

We analyzed the fractal dimension (Df) of lung gas and blood distribution imaged with synchrotron radiation K-edge subtraction (KES), in six anesthetized adult New Zealand White rabbits. KES imaging was performed in upright position during stable Xe gas (64% in O2) inhalation and iodine infusion (Iomeron, 350 mg/mL), respectively, at baseline and after induced bronchoconstriction by aerosolized methacholine (125 mg/mL, 90 s) and bronchodilator (salbutamol, 10 mg/mL, 90 s) inhalation, at two axial image levels. Lung Xe and iodine images were segmented, and maps of regional lung gas and blood fractions were computed. The Df of lung gas (DfXe) and blood (DfIodine) distribution was computed based on a log-log plot of variation coefficient as a function of region volume. DfXe decreased significantly during bronchoconstriction (P < 0.0001), and remained low after salbutamol. DfIodine depended on the axial image level (P < 0.0001), but did not change with bronchoconstriction. DfXe was significantly associated with arterial [Formula: see text] (R = 0.67, P = 0.002), and negatively associated with [Formula: see text] (R = -0.62, P = 0.006), respiratory resistance (R = -0.58, P = 0.011), and elastance (R = -0.55, P = 0.023). These data demonstrate the reduced Df of gas distribution during acute bronchoconstriction, and the association of this parameter with physiologically meaningful variables. This finding suggests a decreased complexity and space-filling properties of lung ventilation during bronchoconstriction, and could serve as a functional imaging biomarker in obstructive airway diseases.NEW & NOTEWORTHY Here, we used an energy-subtractive imaging technique to assess the fractal dimension (Df) of lung gas and blood distribution and the effect of acute bronchoconstriction. We found that Df of gas significantly decreases in bronchoconstriction. Conversely, Df of blood exhibits gravity-dependent changes only, and is not affected by acute bronchoconstriction. Our data show that the fractal dimension of lung gas detects the emergence of clustered rather than scattered loss of ventilatory units during bronchoconstriction.

Fractal analysis reveals functional unit of ventilation in the lung.

Ventilation is inhomogeneous in the lungs across species. It has been hypothesized that ventilation inhomogeneity is largely determined by the design of the airway branching network. Because exchange of gases at the alveolar barrier is more efficient when gas concentrations are evenly distributed at subacinar length scales, it is assumed that a 'functional unit' of ventilation exists within the lung periphery, where gas concentration becomes uniform. On the other hand, because the morphology of pulmonary airways and alveoli, and the distribution of inhaled fluorescent particles show self-similar fractal properties over a wide range of length scales, it has been predicted that fractal dimension of ventilation approaches unity within an internally homogeneous functional unit of ventilation. However, the existence of such a functional unit has never been demonstrated experimentally due to lack of in situ gas concentration measurements of sufficient spatial resolution in the periphery of a complex bifurcating network. Here, using energy-subtractive synchrotron radiation tomography, we measured the distribution of an inert gas (Xe) in the in vivo rabbit lung during Xe wash-in breathing manoeuvres. The effects of convective flow rate, diffusion and cardiac motion were also assessed. Fractal analysis of resulting gas concentration and tissue density maps revealed that fractal dimension was always smaller for Xe than for tissue density, and that only for the gas, a length scale existed where fractal dimension approached unity. The length scale where this occurred was seen to correspond to that of a rabbit acinus, the terminal structure comprising only alveolated airways. KEY POINTS: Gas ventilation is inhomogeneous in the lung of many species. However, it is not known down to what length scales this inhomogeneity persists. It is generally assumed that ventilation becomes homogeneous at subacinar length scales, beyond the spatial resolution of commonly available imaging techniques, hence this has not been demonstrated experimentally. Here we measured the distribution of inhaled Xe gas in the rabbit lung using synchrotron radiation energy-subtractive imaging and used fractal analysis to show that ventilation becomes internally uniform within regions about the size of rabbit lung acini.

Physiologically variable ventilation reduces regional lung inflammation in a pediatric model of acute respiratory distress syndrome.

BACKGROUND: Benefits of variable mechanical ventilation based on the physiological breathing pattern have been observed both in healthy and injured lungs. These benefits have not been characterized in pediatric models and the effect of this ventilation mode on regional distribution of lung inflammation also remains controversial. Here, we compare structural, molecular and functional outcomes reflecting regional inflammation between PVV and conventional pressure-controlled ventilation (PCV) in a pediatric model of healthy lungs and acute respiratory distress syndrome (ARDS). METHODS: New-Zealand White rabbit pups (n = 36, 670 ± 20 g [half-width 95% confidence interval]), with healthy lungs or after induction of ARDS, were randomized to five hours of mechanical ventilation with PCV or PVV. Regional lung aeration, inflammation and perfusion were assessed using x-ray computed tomography, positron-emission tomography and single-photon emission computed tomography, respectively. Ventilation parameters, blood gases and respiratory tissue elastance were recorded hourly. RESULTS: Mechanical ventilation worsened respiratory elastance in healthy and ARDS animals ventilated with PCV (11 ± 8%, 6 ± 3%, p < 0.04), however, this trend was improved by PVV (1 ± 4%, - 6 ± 2%). Animals receiving PVV presented reduced inflammation as assessed by lung normalized [18F]fluorodeoxyglucose uptake in healthy (1.49 ± 0.62 standardized uptake value, SUV) and ARDS animals (1.86 ± 0.47 SUV) compared to PCV (2.33 ± 0.775 and 2.28 ± 0.3 SUV, respectively, p < 0.05), particularly in the well and poorly aerated lung zones. No benefit of PVV could be detected on regional blood perfusion or blood gas parameters. CONCLUSIONS: Variable ventilation based on a physiological respiratory pattern, compared to conventional pressure-controlled ventilation, reduced global and regional inflammation in both healthy and injured lungs of juvenile rabbits.

Effect of nasal airway nonlinearities on oscillometric resistance measurements in infants.

Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow (V')-dependent changes. We employed intrabreath oscillometry in casts of the upper airways constructed from head CT images of 46 infants. We examined oscillometric nasal resistance (Rn) in upper airway casts with no respiratory flow (R0) and the effect of varying V' on Rn by simulating tidal breathing. A characteristic nonlinear relationship was found between Rn and V', exhibiting segmental linearity and a prominent breakpoint (V'bp) after log-log transformation. V'bp was linearly related to the preceding value of end-expiratory volume acceleration (V″eE; on average r2 = 0.96, P < 0.001). Rn depended on V', and R at end-expiration (ReE) showed a strong dependence on V″eE in every cast (r2 = 0.994, P < 001) with considerable interindividual variability. The intercept of the linear regression of ReE versus V″eE was found to be a close estimate of R0. These findings were utilized in reanalyzed Rrs data acquired in vivo in a small group of infants (n = 15). Using a graphical method to estimate R0 from ReE, we found a relative contribution of V'-dependent nonlinearity to total resistance of up to 33%. In conclusion, we propose a method for correcting the acceleration-dependent nonlinearity error in ReE. This correction can be adapted to estimate R0 from a single intrabreath oscillometric measurement, which would reduce the masking effects of the upper airways on the changes in the intrathoracic resistance.NEW & NOTEWORTHY Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow acceleration-dependent distortions. Here, we propose a method for correcting flow acceleration-dependent nonlinearity error based on in vitro measurements in 3D-printed upper airway casts of infants as well as in vivo measurements. This correction can be adapted to estimate Rrs from a single intrabreath oscillometric measurement.

Individual Airway Closure Characterized In Vivo by Phase-Contrast CT Imaging in Injured Rabbit Lung.

OBJECTIVES: Airway closure is involved in adverse effects of mechanical ventilation under both general anesthesia and in acute respiratory distress syndrome patients. However, direct evidence and characterization of individual airway closure is lacking. Here, we studied the same individual peripheral airways in intact lungs of anesthetized and mechanically ventilated rabbits, at baseline and following lung injury, using high-resolution synchrotron phase-contrast CT. DESIGN: Laboratory animal investigation. SETTING: European synchrotron radiation facility. SUBJECTS: Six New-Zealand White rabbits. INTERVENTIONS: The animals were anesthetized, paralyzed, and mechanically ventilated in pressure-controlled mode (tidal volume, 6 mL/kg; respiratory rate, 40; FIO2, 0.6; inspiratory:expiratory, 1:2; and positive end-expiratory pressure, 3 cm H2O) at baseline. Imaging was performed with a 47.5 × 47.5 × 47.5 µm voxel size, at positive end-expiratory pressure 12, 9, 6, 3, and 0 cm H2O. The imaging sequence was repeated after lung injury induced by whole-lung lavage and injurious ventilation in four rabbits. Cross-sections of the same individual airways were measured. MEASUREMENTS AND MAIN RESULTS: The airways were measured at baseline (n = 48; radius, 1.7 to 0.21 mm) and after injury (n = 32). Closure was observed at 0 cm H2O in three of 48 airways (6.3%; radius, 0.35 ± 0.08 mm at positive end-expiratory pressure 12) at baseline and five of 32 (15.6%; radius, 0.28 ± 0.09 mm) airways after injury. Cross-section was significantly reduced at 3 and 0 cm H2O, after injury, with a significant relation between the relative change in cross-section and airway radius at 12 cm H2O in injured, but not in normal lung (R = 0.60; p < 0.001). CONCLUSIONS: Airway collapsibility increases in the injured lung with a significant dependence on airway caliber. We identify "compliant collapse" as the main mechanism of airway closure in initially patent airways, which can occur at more than one site in individual airways.

Change in capnogram waveform is associated with bronchodilator response and asthma control in children.

BACKGROUND: Airway hyper-reactivity, inflammation and remodeling contribute to inhomogeneity of ventilation-perfusion ratio VA·/Q· in asthma. Short-term variations in V.A/Q· can cause changes in expired capnographic indices. OBJECTIVES: To measure acute changes in the phase 3 slope of the volumetric capnogram after ß2-agonist inhalation (ΔSIII), for comparison with airway response based on FEV1 (ΔFEV1), and asthma control. SUBJECTS AND METHODS: After ethical approval and informed consent, 72 children aged 6-18 y, followed up for asthma underwent spirometry and capnography before and after ß-agonist inhalation through a spacer, using a side-stream rapid infrared analyzer. Asthma control was assessed using the GINA questionnaire. RESULTS: Children with positive reversibility tests (defined as ΔFEV1>12%) had a significantly higher ΔSIII (m ± SE: 87.4 ± 41.4) versus those with negative tests (31.3 ± 14.0%, P = 0.001). Uncontrolled asthma was associated with a significantly larger ΔSIII (103.4 ± 64.0%, n = 7) compared to partly controlled (52.0 ± 26.1, n = 24; P = 0.009) and controlled asthma (30.8 ± 16.3, n = 41; P = 0.003). Neither Bohr dead space nor ΔFEV1 were different between asthma control groups. CONCLUSIONS: ΔSIII was significantly larger in children with positive response to ß2-agonist, and in uncontrolled asthmatics. To our knowledge these are the first data on exhaled CO2 phase III volumetric slope change and asthma control. The observed ΔSIII could be due to an increased ventilation of inhomogeneous peripheral lung units, and merits further evaluation as a potential phenotypic biomarker in asthma.

Failing to meet relative humidity targets for incubated neonates causes higher heat loss and metabolic costs in the first week of life.

AIM: Frequent nursing procedures can modify a newborn infant's thermal environment when their incubator is opened. This study evaluated the impact of relative humidity (RH) on preterm infants in closed incubators and calculated their heat loss and additional metabolic cost. METHODS: We studied 45 preterm infants born before 32 + 0 weeks, nursed at the neonatal intensive care unit at Amiens University Hospital, France from January 2009 to November 2011. Their body, skin and air temperatures and the incubator's RH were continuously recorded from day 1 to 8 of life, and the differences between the measured and target RH were calculated. Body heat loss (BHL) was also calculated. RESULTS: On day one, the measured RH (68.7 ± 1.0%) was significantly lower than the target RH (75%, p < 0.05), but this difference, together with BHL (p < 0.001) and evaporative heat loss (p < 0.001), fell significantly over time (p < 0.05). The additional metabolic cost correlated with the difference between measured and target RH (p < 0.001). CONCLUSION: RH from day 1 to 8 was below the recommended target value for preterm infants and resulted in high evaporative and greater total BHL and additional metabolic cost. The findings pose numerous challenges, including nursing care and incubator design.

Synchrotron Imaging Shows Effect of Ventilator Settings on Intrabreath Cyclic Changes in Pulmonary Blood Volume.

Despite the importance of dynamic changes in the regional distributions of gas and blood during the breathing cycle for lung function in the mechanically ventilated patient, no quantitative data on such cyclic changes are currently available. We used a novel gated synchrotron computed tomography imaging to quantitatively image regional lung gas volume (Vg), tissue density, and blood volume (Vb) in six anesthetized, paralyzed, and mechanically ventilated rabbits with normal lungs. Images were repeatedly collected during ventilation and steady-state inhalation of 50% xenon, or iodine infusion. Data were acquired in a dependent and nondependent image level, at zero end-expiratory pressure (ZEEP) and 9 cm H2O (positive end-expiratory pressure), and a tidal volume (Vt) of 6 ml/kg (Vt1) or 9 ml/kg (Vt2) at an Inspiratory:Expiratory ratio of 0.5 or 1.7 by applying an end-inspiratory pause. A video showing dynamic decreases in Vb during inspiration is presented. Vb decreased with positive end-expiratory pressure (P = 0.006; P = 0.036 versus Vt1-ZEEP and Vt2-ZEEP, respectively), and showed larger oscillations at the dependent image level, whereas a 45% increase in Vt did not have a significant effect. End-inspiratory Vb minima were reduced by an end-inspiratory pause (P = 0.042, P = 0.006 at nondependent and dependent levels, respectively). Normalized regional Vg:Vb ratio increased upon inspiration. Our data demonstrate, for the first time, within-tidal cyclic variations in regional pulmonary Vb. The quantitative matching of regional Vg and Vb improved upon inspiration under ZEEP. Further study is underway to determine whether these phenomena affect intratidal gas exchange.

Dynamic Mechanical Interactions Between Neighboring Airspaces Determine Cyclic Opening and Closure in Injured Lung.

OBJECTIVES: Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. DESIGN: Experimental animal study. SETTING: International synchrotron radiation laboratory. SUBJECTS: Four anesthetized rabbits, ventilated in pressure controlled mode. INTERVENTIONS: The lung was consecutively imaged at ~ 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end-expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (Fderecruited, Frecruited) were computed based on the comparison of the aerated volumes at successive time points. MEASUREMENTS AND MAIN RESULTS: Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of Fderecruited and Frecruited when mechanical interdependence was included, while its exclusion gave Frecruited values of zero at positive end-expiratory pressure greater than or equal to 3 cm H2O. CONCLUSIONS: These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage.

CT density distribution analysis in patients with cystic fibrosis: correlation with pulmonary function and radiologic scores.

RATIONALE AND OBJECTIVES: The progressive changes in lung morphology observed in cystic fibrosis (CF) can potentially affect the statistical distribution of computed tomography (CT) density values. This study aimed to characterize the lung CT density distributions by quantifying indices of the kurtosis and skewness of the lung density distribution and to compare these indices to radiologic scores and lung function parameters in children and young adults with CF. MATERIALS AND METHODS: CT scans and lung function of 26 patients with CF were retrospectively examined. The Bhalla radiologic scoring was performed separately, in random order, by two expert radiologists, blinded to the patient's identity, age, clinical status, results of lung function tests, and the other paired observer's score. RESULTS: Positive relations were evidenced between the log indices of lung density distribution kurtosis (iKurtosis) and the overall radiologic scores (RS) of both observers (R = 0.58; P < .001 vs RS1 and R = 0.71; P < .001 vs RS2). A similar relationship was evidenced with the log index of the degree of distribution asymmetry (iSkewness; R = 0.62; P < .001 vs RS1 and R = 0.62; P < .001 vs RS2). Log-iKurtosis and log-iSkewness were related to FEV1 (R = -0.56; P < 10(-5) and R = -0.55; P < 10(-5)) and to residual volume (R = 0.40; P < .001 and R = 0.45; P < .001, respectively). Both radiologic scores showed significant relation with lung function. The correlation between RS1 and RS2 was excellent (R = 0.93), with a Cohen weighted kappa of 0.43. CONCLUSIONS: Characteristic indices of lung CT density distribution are correlated to lung function and radiologic scores in patients with CF and merit further evaluation as part of more comprehensive automated methods for quantifying CF lung CT data.

Polyethylene bag wrapping to prevent hypothermia during percutaneous central venous catheter insertion in the preterm newborn under 32 weeks of gestation.

AIM: In preterm neonates, during nursing procedures, body temperature decreases. This study evaluates the interest of polyethylene bag wrapping to prevent this decrease during percutaneous central venous catheter (PCVC) insertion procedure, in preterm neonates under 32 weeks of gestation nursed in closed incubators. METHODS: This prospective observational study compared two periods: [May 2009-September 2009]: "without polyethylene bag wrapping" and [October 2009-March 2010]: "with polyethylene bag wrapping". The main criterion was newborn skin temperature at the end of the procedure. RESULTS: There was no difference between the two groups for skin temperature before the procedure (36.9 ± 0.3 °C versus 36.9 ± 0.3 °C; p = NS). The skin temperature at the end of the procedure was lower in the "without bag wrapping" group (36.0 ± 0.5 °C) compared to the "bag wrapping" group (36.4 C ± 0.5 °C; p = 0.01). Furthermore, no skin temperature at the end was higher than 37.4 °C in the bag wrapping group. CONCLUSION: The use of a polyethylene bag was effective in decreasing skin temperature fall during a PCVC insertion procedure in our population. No side effects were observed. The benefit of prolonged wrapping or for shorter procedure should be evaluated.

Assessment of radiant temperature in a closed incubator.

In closed incubators, radiative heat loss (R) which is assessed from the mean radiant temperature (Tr) accounts for 40-60% of the neonate's total heat loss. In the absence of a benchmark method to calculate Tr--often considered to be the same as the air incubator temperature-errors could have a considerable impact on the thermal management of neonates. We compared Tr using two conventional methods (measurement with a black-globe thermometer and a radiative "view factor" approach) and two methods based on nude thermal manikins (a simple, schematic design from Wheldon and a multisegment, anthropometric device developed in our laboratory). By taking the Tr estimations for each method, we calculated metabolic heat production values by partitional calorimetry and then compared them with the values calculated from V(O2) and V(CO2) measured in 13 preterm neonates. Comparisons between the calculated and measured metabolic heat production values showed that the two conventional methods and Wheldon's manikin underestimated R, whereas when using the anthropomorphic thermal manikin, the simulated versus clinical difference was not statistically significant. In conclusion, there is a need for a safety standard for measuring TR in a closed incubator. This standard should also make available estimating equations for all avenues of the neonate's heat exchange considering the metabolic heat production and the modifying influence of the thermal insulation provided by the diaper and by the mattress. Although thermal manikins appear to be particularly appropriate for measuring Tr, the current lack of standardized procedures limits their widespread use.

Relationship between functional residual capacity and oxygen desaturation during short central apneic events during sleep in "late preterm" infants.

Apneic episodes are frequent in the preterm neonate and particularly in active sleep (AS), when functional residual capacity (FRC) can be decreased. Furthermore, FRC may be inversely correlated with the speed of blood-O(2)-desaturation. We evaluated the potential involvement of FRC in the mechanisms responsible for blood-O(2)-desaturation during short central apneic events (>3 s) in "late-preterm" infants and analyzed the specific influence of sleep state. Apneic events were scored in 29 neonates (postmenstrual age: 36.1 +/- 1.2 wk) during AS and quiet sleep (QS). FRC was measured during well-established periods of regular breathing. Apneas with blood-O(2)-desaturation (drop in SpO(2) >5% from the baseline, lowest SpO(2) during apnea: 91.4 +/- 1.8%) were more frequent in AS than in QS, whereas no difference was seen for apneas without desaturation. The magnitude of the FRC did not depend on the sleep state. In AS only, there was a negative relationship between FRC and the proportion of apneas with desaturation. Even in late preterm infants who do not experience long-lasting apnea, blood-O(2)-desaturation during short apneic events is related (in AS but not QS) to a low baseline FRC. Sleep stage differences argue for a major role of AS-related mechanisms in the occurrence of these apneas.

A reproducible means of assessing the metabolic heat status of preterm neonates.

The aim of the present study was to validate the measurement of metabolic heat production using partitional calorimetry (PC) in preterm neonates exposed to a near-thermoneutral environment in an incubator. In order to reduce experimental uncertainty (due to the different variables involved in the calculation of body heat exchanges between the infant and the environment), the mean radiant temperature and the heat transfer coefficients for convection, radiation and evaporation were measured using a multisegment, anthropometric thermal mannequin which represents a small-for-gestational-age neonate (body surface area: 0.150 m2; simulated birth weight: 1500 g). The metabolic heat production calculated by PC was compared with the results of indirect respiratory calorimetry, which is rarely done in clinical setting since this method interferes with the neonate's environment and requires a high degree of technical preparedness. The oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in 20 preterm neonates exposed to thermoneutral (32.3 degrees C) and to slightly cool environments (30.2 degrees C). The mean skin temperature was measured by infrared thermography. The measurements were made during well-established periods of active and quiet sleep. Metabolic heat production was assessed by weighting each value of VO2 and VCO2 by the duration of the sleep stages. Our results showed that there was no significant difference between the two methods in terms of their estimation of metabolic activity at thermoneutrality (mean overall difference: 0.34 kJ h(-1) kg(-1)) and in the cool environment (0.26 kJ h(-1) kg(-1)). We observed significant interneonate variability. Partitional calorimetry enabled the prediction of body growth with a daily error of less than 5.3 g (2.38 kJ h(-1) kg(-1)) for all the neonates at thermoneutrality and for 85% of the subjects (3.03 kJ h(-1) kg(-1)) in the cool environment. Despite this limitation, we demonstrate here that PC provides reliable information for calculating the energy expenditure of individual preterm neonates on the basis of standard environmental input variables. We suggest that the technique can be advantageously used to assess the energy expenditure and normal growth of these infants.