Measuring lung function in murine models of pulmonary disease

Mice are commonly used to model human lung diseases. However, their small size poses substantial problems for accurately measuring lung function. Noninvasive techniques have been widely used but have severe limitations and should be restricted to screening for the presence of disease. Accurate measures of lung function and assessment of the site of disease pathology and drug action are possible using invasive techniques. Investigators must understand the strengths and weaknesses of each technique before deciding which to use

Negative impact of the noseclip on high-frequency respiratory impedance measurements

The noseclip is conventionally used in lung function testing to prevent leakage via the nasal compartments. However, some subjects exhibit a velum-opening reflex which may affect results. We performed forced oscillation measurements at frequencies (8–256 Hz) that include the first antiresonance, comparing the noseclip with a cotton wool nose plug to eliminate upper airway contribution. Three sets of measurements were made in 18 adults: with and without noseclip, and with cotton wool. Velum opening during noseclip measurements was monitored using a nasal pressure transducer. A significantly greater proportion of subjects produced a characteristic distortion to the first antiresonance with the noseclip than with either no noseclip or with cotton wool. Distortion of the spectrum coincided with the transmission of oscillations into the nasal cavity. Thus, the noseclip cannot be used in high-frequency forced oscillation measurements because of the velum reflex. The cotton wool plug offers a simple alternative. This effect has unknown impact in other lung function tests

Changes in functional residual capacity and lung mechanics during surgical repair of congenital heart diseases: effects of preoperative pulmonary hemodynamics

BACKGROUND: To characterize the impact of lung volume changes in the lung function impairment after the surgical repair of congenital heart diseases, combined measurements of functional residual capacity, lung clearance index, and respiratory mechanics were performed in children with hypoperfused lungs (tetralogy of Fallot [TOF]) or with pulmonary hyperperfusion (ventricular septal defect [VSD]). METHODS: Lung volume and clearance were assessed by using a sulfur hexafluoride washout technique, and the mechanical properties of the respiratory system were assessed using a low-frequency oscillation technique. Lung volume and oscillatory measurements were made preoperatively, before and after cardiopulmonary bypass and aortic clamping (AC), and after chest closure. RESULTS: Impairments in airway (36 +/- 2%) and tissue mechanics (22 +/- 3%) were observed in the children with TOF after bypass; AC and chest closure were associated with marked decreases in functional residual capacity (-24 +/- 3% and -13 +/- 2% for TOF and VSD after AC, respectively) and increases in lung clearance index (-60 +/- 6% and -24 +/- 3% for TOF and VSD after AC, respectively). Smaller impairments in lung mechanics were observed after bypass and AC in children with VSD. CONCLUSIONS: These findings suggest that the lung volume loss and lung mechanical deteriorations are probably caused by a diminished tethering effect of the lung periphery through a reduced filling of the pulmonary capillaries. This effect seems to be more pronounced in children with hypoperfused lungs (TOF) than in those with pulmonary hyperperfusion (VSD). The beneficial postoperative changes in children with VSD are consequences of the reversal of the pulmonary vascular engorgement after surgical repair

Low frequency forced oscillation technique in infants

The respiratory system in infants undergoes profound changes in the first few years of life. We applied two adaptions of the FOT to characterise 1 ) changes in airway and parenchymal mechanics with growth in the first two years of life; 2) contribution of the nose to total respiratory impedance (Zrs); and 3) the influence of the chest wall to Zrs. Methods: For studies 1 (n=34, 1 -24 months) & 2 (n=20, 3-21 months) a pseudo-random forcing signal (0.5-21 Hz) was applied to sedated infants via a face mask & Zrs was determined at a transrespiratory pressure of 20cm HzO. A model containing an airway compartment [airway resistance (R) & inertance (I)] & a frequency dependant constant-phase tissue compartment [tissue damping (G) & tissue elastance (H)] was fitted to Zrs. In the second study, Zrs was partitioned into nasal impedance (Zn) & lower respiratory system impedance (Zlrs). In the third study, Zrs & chest wall impedance (Zw) were determined at FRC in patients undergoing cardiac surgery (n=5, 3-7.5 years). Lung impedance (Zl) was calculated as Zl = Zrs - Zw. Results: In infants with no history of lung disease the growth of the airways was found to lag that of the pulmonary tissues. Zn contributed 42.5±4.4(SEM)% and 73.4±6.7% of the total R & I respectively, however it's contribution to the total G and H was negligible. The chest wall contributed substantially to the parenchymal parameters of total respiratory G (46.5±6.7%) & H (39.9±7.4%) while having negligible influence on R & I of the total respiratory system. Conclusions: The different growth patterns of the airways and parenchyma support the concept of dysanaptic growth in this population. The relative contribution of Zn to Zrs for all parameters was constant with growth, however the relative resistive and elastic properties of the chest wall decreased with age. In summary the FOT allows changes in airway and parenchymal mechanics to be examined in infants and young children

Dependence of intrapulmonary pressure amplitudes on respiratory mechanics during high-frequency oscillatory ventilation in preterm lambs

In the healthy animal lung, high-frequency oscillatory ventilation (HFOV) achieves effective ventilation at tidal volumes (V-T) less than or equal to dead space while generating very small pressure fluctuations in the alveolar spaces (DeltaP(A)). We hypothesized that the respiratory mechanical parameters influence the magnitude of the intrapulmonary pressure fluctuations during HFOV. A computer model of the neonatal respiratory system was used to examine the independent effects of altering the compliance, nonlinear and linear resistance, and inertance of the respiratory system on V-T, and cyclic intrapulmonary pressures under homogeneous and heterogeneous conditions. The impact of low compliance on the transmission of pressure from the airway opening to the trachea (DeltaP(tr)/DeltaP(ao)) and alveolar compartment (DeltaP(A)/DeltaP(ao)) during HFOV was determined in a preterm lamb lung model. In the computer model, an increase in flow-dependent resistance to simulate changing the internal diameter of the tracheal tube from 4.0 nun to 2.5 mm halved the transmission of the pressure waveform to both the carina and the alveolar compartment. Increased peripheral resistance was associated with an increased DeltaP(tr)/DeltaP(ao) but a reduction in DeltaP(A)/DeltaP(ao). The DeltaP(A)/DeltaP(ao) also decreased with increasing alveolar compartment compliance, a finding that was verified in the preterm lamb lung. There was an exponential decrease in the magnitude of DeltaP(A1) compared with DeltaP(A2) as the ratio of the time constants of the two parallel compartments (tau(1)/tau(2)) increased in the heterogeneous computer lung model. The transmission of driving pressure amplitude to both the proximal airways and lung tissue during HFOV is dependent on lung mechanics and may be greater in the poorly compliant lung than that observed previously in experiments on healthy animals

Desflurane but not sevoflurane impairs airway and respiratory tissue mechanics in children with susceptible airways

BACKGROUND: Although sevoflurane and desflurane exert bronchoactive effects, their impact on the airway and respiratory tissue mechanics have not been systematically compared in children, especially in those with airway susceptibility (AS). The aim of this study was to assess airway and respiratory tissue mechanics in children with and without AS during sevoflurane and desflurane anesthesia. METHODS: Respiratory system impedance was measured in healthy control children (group C, n = 20) and in those with AS (group AS, n = 20). Respiratory system impedance was determined during propofol anesthesia and during inhalation of sevoflurane and desflurane 1 minimum alveolar concentration in random order. Airway resistance, tissue damping, and elastance were determined from the respiratory system impedance spectra by model fitting. RESULTS: Children in group AS exhibited significantly higher respiratory impedance parameters compared with those in group C. Sevoflurane slightly decreased airway resistance (-7.0 +/- 1.5% vs. -4.8 +/- 2.4% in groups C and AS, respectively) in both groups. In contrast, desflurane caused elevations in airway resistance and tissue mechanical parameters, with markedly enhanced airway narrowing in children with AS (18.2 +/- 2.8% vs. 53.9 +/- 5%; P < 0.001 for airway resistance in groups C and AS, respectively). Neither the order of drug administration nor the time after the establishment of their steady state concentrations affected these findings. CONCLUSIONS: These results emphasized the deleterious effects of desflurane on the airways, particularly in children with susceptible airways in contrast with the consistent beneficial effects of sevoflurane, questioning the use of desflurane in children with AS

Lung mechanical and vascular changes during positive- and negative-pressure lung inflations: importance of reference pressures in the pulmonary vasculature

The continuous changes in lung mechanics were related to those in pulmonary vascular resistance (Rv) during lung inflations to clarify the mechanical changes in the bronchoalveolar system and the pulmonary vasculature. Rv and low-frequency lung impedance data (Zl) were measured continuously in isolated, perfused rat lungs during 2-min inflation-deflation maneuvers between transpulmonary pressures of 2.5 and 22 cmH(2)O, both by applying positive pressure at the trachea and by generating negative pressure around the lungs in a closed box. ZL was averaged and evaluated for 2-s time windows; airway resistance (Raw), parenchymal damping and elastance (H) were determined in each window. Lung inflation with positive and negative pressures led to very similar changes in lung mechanics, with maximum decreases in Raw [-68 +/- 4 (SE) vs. -64 +/- 18%] and maximum increases in H (379 +/- 36 vs. 348 +/- 37%). Rv, however, increased with positive inflation pressure (15 +/- 1%), whereas it exhibited mild decreases during negative-pressure expansions (-3 +/- 0.3%). These results demonstrate that pulmonary mechanical changes are not affected by the opposing modes of lung inflations and confirm the importance of relating the pulmonary vascular pressures in interpreting changes in Rv

Linking lung function and inflammatory responses in ventilator-induced lung injury

Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field