Congenital malformation of lung parenchyma: 15 years experience in a thoracic surgical unit.

OBJECTIVE: To review the surgical management of congenital malformations of lung parenchyma in a thoracic surgery unit over a period of 15 years. METHODS: We carried out a retrospective analysis of records of all patients who had surgery for congenital malformations of lung parenchyma between 1995 and 2010. RESULTS: Forty-five patients underwent surgery for congenital lung lesions out of 3735 thoracotomies performed during the study period. The lesions included 29 lung sequestrations, 12 bronchogenic cysts, 3 congenital lobar emphysema and one congenital cystic adenomatoid malformation. Only 26 (26%) cases were diagnosed preoperatively. Twenty-eight (62.2%) patients underwent lobectomy, 5 (11.1%) patients had pneumonectomy, and 10 (22.2%) patients had removal of cyst while 2 (0.45%) patients had lung resection with repair of the oesophageal connection. No mortality was recorded. One patient had post-operative complication of oesophageal fistula which was successfully managed conservatively. The follow-up was between 8 months to 14 years. All patients were asymptomatic and had no physical limitations during the follow-up. CONCLUSIONS: Surgery is curative and produces good long-term result in patients with congenital malformations of lung parenchyma. It should be offered to patients as a therapeutic option where indicated and feasible.

Elucidation of relationship between tumor size and survival in non-small-cell lung cancer patients can aid early decision making in clinical drug development.

Four non-small-cell lung cancer (NSCLC) registration trials were utilized to develop models linking survival to risk factors and changes in tumor size during treatment. The purpose was to leverage existing quantitative knowledge to facilitate future development of anti-NSCLC drugs. Eleven risk factors were screened using a Cox model. A mixed exponential decay and linear growth model was utilized for modeling tumor size. Survival times were described in a parametric model. Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size were consistent prognostic factors of survival. Tumor size was well described by the mixed model. The parametric survival model includes ECOG score, baseline tumor size, and week 8 tumor size change as predictors of survival duration. The change in tumor size at week 8 allows early assessment of the activity of an experimental regimen. The survival model and the tumor model will be beneficial for early screening of candidate drugs, simulating NSCLC trials, and optimizing trial designs.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Respiratory system responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.

Active, nonanesthetized, tracheotomized rabbits were subjected to continuous positive airway pressure (CPAP) for 4 days to determine the effects of chronic mechanical strain on lung and airway function. Rabbits were maintained for 4 days at a CPAP of 6 cmH(2)O (high CPAP), at a CPAP of 0 cmH(2)O (low CPAP), or without tracheostomy (no CPAP). After treatment with CPAP, changes in respiratory resistance in response to increasing concentrations of inhaled ACh were measured during mechanical ventilation to evaluate respiratory system responsiveness in vivo. Intraparenchymal bronchial segments were isolated from the lungs of all animals to evaluate airway smooth muscle responsiveness and bronchial compliance in vitro. Rabbits maintained for 4 days at high CPAP demonstrated significantly lower responsiveness to ACh compared with rabbits that were maintained at low CPAP or with no CPAP. Airways isolated from the lungs of animals subjected to the chronic application of high CPAP were also less responsive to ACh in vitro than the airways isolated from animals subjected to low CPAP or no CPAP. The persistence of the decreased responsiveness in the excised airway tissues suggests that the decreased respiratory system responsiveness observed in vivo results primarily from direct effects on the airways. The results demonstrate that the application of prolonged mechanical strain in vivo can reduce airway reactivity.

Chronic strain alters the passive and contractile properties of rabbit airways.

Pathophysiological conditions of the lung may shift the balance of forces so as to chronically alter the amount of strain imposed on the airways. This chronic strain could result in changes in the structure and/or function of the airways that affect its physiological properties. We evaluated the effects of imposing physiological levels of chronic mechanical strain on the passive and active physiological properties of intraparenchymal rabbit airways. Isolated bronchial segments were cultured for 48 h at transmural pressures of 0 cmH(2)O (No Strain) or 7 cmH(2)O (Strain). Effects of strain on small parenchymal airways were evaluated in lung tissue slices cultured under conditions of No Strain or approximately 50% increased in diameter (Strain). Chronic strain resulted in a higher passive compliance of the bronchial segments and larger airway lumen size. In addition, bronchi not subjected to chronic Strain were more responsive to ACh than bronchi subjected to chronic Strain, and airways in lung slices subjected to No Strain narrowed more in response to ACh than airways in lung slices subjected to Strain. The greatest effects of chronic strain occurred in the smallest sized airways. Our results suggest that chronic distension of the airways has physiologically important effects on their passive and active properties, which are most prominent in the smaller, more peripheral airways.

Comparison of elastic properties and contractile responses of isolated airway segments from mature and immature rabbits.

Immature rabbits have greater maximal airway narrowing with bronchoconstriction in vivo compared with mature animals. As isolated immature lungs have a lower shear modulus, it is unclear whether the greater airway narrowing in the immature lung is secondary to less tethering between the airways and the lung parenchyma or to differences in the mechanical properties of the mature and immature airways. In the present study, we compared the mechanical properties of fluid-filled, isolated, intraparenchymal airway segments of the same generation from mature and immature rabbits. Stimulation with ACh resulted in greater airway narrowing in immature than mature bronchi. The immature bronchi were more compliant, had a lower resting airway volume, and were more collapsible compared with the mature bronchi. When the airways were contracted with ACh under isovolume conditions, the immature bronchi generated greater active pressure, and they were more sensitive to ACh than were mature bronchi. Our results suggest that maturational differences in the structure and function of the airways in the absence of the lung parenchyma can account for the greater maximal narrowing of immature than mature airways in vivo.

Computational model of airway narrowing: mature vs. immature rabbit.

Immature rabbits have greater maximal airway narrowing and greater maximal fold increases in airway resistance during bronchoconstriction than mature animals. We have previously demonstrated that excised immature rabbit lungs have more distensible airways, a lower shear modulus, and structural differences in the relative composition and thickness of anatomically similar airways. In the present study, we incorporated anatomic and physiological data for mature and immature rabbits into a computational model of airway narrowing. We then investigated the relative importance of maturational differences in these factors as determinants of the greater airway narrowing that occurs in the immature animal. The immature model demonstrated greater sensitivity to agonist, as well as a greater maximal fold increase in airway resistance. Exchanging values for airway compliance between the mature and immature models resulted in the mature model exhibiting a greater maximal airway response than the immature model. In contrast, exchanging the shear moduli or the composition of the airway wall relative to the airway size produced relatively small changes in airway reactivity. Our results strongly suggest that the mechanical properties of the airway, i.e., greater compliance of the immature airway, can be an important factor contributing to the greater airway narrowing of the immature animal.

Bronchoprotective and bronchodilatory effects of deep inspiration in rabbits subjected to bronchial challenge.

The effect of deep inspiration (DI) on airway responsiveness differs in asthmatic and normal human subjects. The mechanism for the effects of DI on airway responsiveness in vivo has not been identified. To elucidate potential mechanisms, we compared the effects of DI imposed before or during induced bronchoconstriction on the airway response to methacholine (MCh) in rabbits. The changes in airway resistance in response to intravenous MCh were continuously monitored. DI depressed the maximum response to MCh when imposed before or during the MCh challenge; however, the inhibitory effect of DI was greater when imposed during bronchoconstriction. Because immature rabbits have greater airway reactivity than mature rabbits, we compared the effects of DI on their airway responses. No differences were observed. Our results suggest that the mechanisms by which DI inhibits airway responsiveness do not depend on prior activation of airway smooth muscle (ASM). These results are consistent with the possibility that reorganization of the contractile apparatus caused by stretch of ASM during DI contributes to depression of the airway response.

Airway branching morphology of mature and immature rabbit lungs.

The scheme of Horsfield et al. for describing the pulmonary airway tree (J Appl Physiol 52: 21-26, 1982) catalogs each airway according to its order and the difference in order of its two daughters (denoted Delta). Although this scheme captures the natural asymmetry in the airway tree, it is still deterministic, because it assumes that all airways of a given order are the same; yet such variability is extremely important in determining the overall behavior of the lungs. We therefore analyzed complete lung lobes from three mature and two immature rabbits and determined the Horsfield order and Delta of every airway down to the terminal bronchioles. We also measured the diameter of each airway. This allowed us to determine the average structure of the rabbit airway tree, the variation about this average, and also how the structures of mature and immature airway trees compare. We found some variation in branching asymmetry and airway diameter at a given order between animals but no evidence of systematic differences in structure between mature and immature lungs. We found evidence of a difference in the branching structure of the peripheral vs. the central part of the airway tree (the break point being around order 20). We also determined the nature of the variation in Delta and diameter as a function of order, which should be valuable for the development of computer models seeking to encapsulate the naturally occurring regional variation in airway geometry in the normal rabbit lung.

Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits.

We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH(2)O. At Ptp > 8 cmH(2)O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH(2)O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH(2)O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH(2)O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 +/- 0.29 vs. 2.23 +/- 0.19). At Ptp of 5 and 2 cmH(2)O, the fold increases in RL were greater for immature than mature animals (13.19 +/- 1.81 vs. 3.89 +/- 0.37) and (17.74 +/- 2.15 vs. 4.6 +/- 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.

Differences in airway structure in immature and mature rabbits.

Our laboratory has previously demonstrated that maximal bronchoconstriction produces a greater degree of airway narrowing in immature than in mature rabbit lungs (33). To determine whether these maturational differences could be related to airway structure, we compared the fraction of the airway wall occupied by airway smooth muscle (ASM) and cartilage, the proportion of wall area internal to ASM, and the number of alveolar attachments to the airways, from mature and immature (6-mo- and 4-wk-old, respectively) rabbit lungs that were formalin fixed at total lung capacity. The results demonstrate that the airway walls of immature rabbits had a greater percentage of smooth muscle, a lower percentage of cartilage, and fewer alveolar attachments compared with mature rabbit airways; however, we did not find maturational differences in the airway wall thickness relative to airway size. We conclude that structural differences in the airway wall may contribute to the greater airway narrowing observed in immature rabbits during bronchoconstriction.

Comparative respiratory system mechanics in rodents.

Because of the wide utilization of rodents as animal models in respiratory research and the limited data on measurements of respiratory input impedance (Zrs) in small animals, we measured Zrs between 0.25 and 9.125 Hz at different levels (0-7 hPa) of positive end-expiratory pressure (PEEP) in mice, rats, guinea pigs, and rabbits using a computer-controlled small-animal ventilator (Schuessler TF and Bates JHT, IEEE Trans Biomed Eng 42: 860-866, 1995). Zrs was fitted with a model, including a Newtonian resistance (R) and inertance in series with a constant-phase tissue compartment characterized by tissue damping (Gti) and elastance (Hti) parameters. Inertance was negligible in all cases. R, Gti, and Hti were normalized to body weight, yielding normalized R, Gti, and Hti (NHti), respectively. Normalized R tended to decrease slightly with PEEP and increased with animal size. Normalized Gti had a minimal dependence on PEEP. NHti decreased with increasing PEEP, reaching a minimum at approximately 5 hPa in all species except mice. NHti was also higher in mice and rabbits compared with guinea pigs and rats at low PEEPs, which we conclude is probably due to a relatively smaller air space volume in mice and rabbits. Our data also suggest that smaller rodents have proportionately wider airways than do larger animals. We conclude that a detailed, comparative study of respiratory system mechanics shows some evidence of structural differences among the lungs of various species but that, in general, rodent lungs obey scaling laws similar to those described in other species.