BACKGROUND: In acute respiratory distress syndrome, pulmonary vascular permeability increases, causing intravascular fluid and protein to move into the lung's interstitium. The classic model describing the formation of pulmonary edema suggests that fluid crossing the capillary endothelium is drawn by negative interstitial pressure into the potential space surrounding extra-alveolar vessels and, as interstitial pressure builds, is forced into the alveolar air space. However, the validity of this model is challenged by animal models of acute lung injury in which extra-alveolar vessels are more permeable than capillaries under a variety of conditions. In the current study, we sought to determine whether extravascular fluid accumulation can be produced because of increased permeability of either the capillary or extra-alveolar endothelium, and whether different pathophysiology results from such site-specific increases in permeability. MATERIALS AND METHODS: We perfused isolated lungs with either the plant alkaloid thapsigargin, which increases extra-alveolar endothelial permeability, or with 4alpha-phorbol 12, 13-didecanoate, which increases capillary endothelial permeability. RESULTS: Both treatments produced equal increases in whole lung vascular permeability, but caused fluid accumulations in separate anatomical compartments. Light microscopy of isolated lungs showed that thapsigargin caused fluid cuffing of large vessels, while 4alpha-phorbol 12, 13-didecanoate caused alveolar flooding. Dynamic compliance was reduced in lungs with cuffing of large vessels, but not in lungs with alveolar flooding. CONCLUSIONS: Phenotypic differences between vascular segments resulted in site-specific increases in permeability, which have different pathophysiological outcomes. Our findings suggest that insults leading to acute respiratory distress syndrome may increase permeability in extra-alveolar or capillary vascular segments, resulting in different pathophysiological sequela.

BACKGROUND: Pathologic changes, including inflammation and remodeling, occur in the asthmatic airway. However, their relative contribution to the components of airway hyperresponsiveness (AHR) remains unclear. OBJECTIVE: Attempting to delineate AHR into discrete immune-mediated and structural remodeling components, we performed a detailed time course of the development, progression, and persistence of maximal respiratory system resistance, airway reactivity, and airway sensitivity. METHODS: Mice exposed to increasing durations of persistent allergen were assessed for airway function, morphometry, and inflammation. RESULTS: Allergen exposure resulted in increases for all indices of AHR that persisted for at least 4 weeks after chronic allergen exposure (P <.01 for all values). Early increases in AHR were associated with increases in immune-mediated events, including airway eosinophils (P <.01), whereas sustained AHR was associated with structural remodeling events. Increased maximal respiratory system resistance, evident by 6 weeks postallergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, was associated with an increase in collagen deposition (P <.01). Increased airway reactivity and sensitivity, each evident by 1 week after allergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, were associated with an increase in airway smooth muscle area (P <.01). CONCLUSION: Our novel observation of distinct temporal relationships in the development, progression, and persistence of the individual indices of AHR supports our hypothesis that multiple underlying factors contribute to airway dysfunction. CLINICAL IMPLICATIONS: These findings illustrate the importance of clearly addressing specific components of airway dysfunction to provide greater insight into specific pathophysiologic mechanisms in airway disease.

Infection/inflammation and mechanical ventilation have both independently been shown to increase cytokine/chemokine levels in lung tissue and blood samples of premature patients. Little is known about the combined effect of systemic inflammation and mechanical ventilation on cytokine expression in the lung. We tested whether pre-existing inflammation induced by lipopolysaccharide (LPS) exposure would modify cytokine/chemokine response in newborn rat lungs to high tidal volume ventilation (HTVV). Newborn rats were randomly assigned to four groups: groups I and II (saline); groups III and IV: 3 mg/kg LPS. Groups II and IV were 24h later subjected to 3h of ventilation with a tidal volume of 25 mL/kg. HTVV alone increased IL-1beta, IL-6 and the chemokine (C-X-C motif) ligand 2 (CXCL2) mRNA expression. Although the cytokine response to LPS alone had disappeared after 24 h, the combination of LPS pretreatment and HTVV significantly increased the expression of IL-6 and IL-1beta mRNA when compared with HTVV alone. TNF-alpha expression was increased neither by HTVV alone nor in combination with LPS. IL-6 protein content in bronchoalveolar lavage increased due to the combined treatment. Thus, a subtle pre-existing inflammation combined with HTVV amplifies the proinflammatory cytokine/chemokine expression in the newborn rat lung compared with HTVV alone. ABBREVIATIONS::

Background: Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, newborn and adult rats were air ventilated at low (10) or high (30 ml/kg) tidal volume and compared to age-matched non-ventilated controls. Methods and Results: Blood was collected at the end of the experiment for measurement of clot time, tissue factor and other coagulation factors content. Similar measurements were obtained from lung lavage material. The newborn clot time (44+/-1) was lower and plasma tissue factor content higher (103.4+/-0.4) than adults (88+/-4 s and 26.6+/-1.4 units; P<0.01). High, but not low tidal volume ventilation of newborns for as little as 15 min significantly reduced clot time and increased plasma tissue factor content (P<0.01). High volume ventilation increased plasma factor Xa (0.1+/-0.1 to 1.6+/-0.4 nM; P<0.01) and thrombin (1.3+/-0.2 to 2.2+/-0.4 nM; P<0.05) and decreased antithrombin (0.12+/-0.01 to 0.05+/-0.01; P<0.01) in the newborn. Lung lavage material of high volume ventilated newborns showed increased (P<0.01) factor Xa and thrombin. No changes in these parameters were observed in adult rats high volume ventilated for up to 90 min. Conclusions: Compared to adults, newborn rats have a greater propensity for volutrauma-activated intravascular coagulation. These data suggest that mechanical ventilation promotes neonatal thrombosis via lung tissue factor release.

It is now well established that passive exposure to inhaled OVA leads to a state of immunological tolerance. Therefore, to elicit allergic sensitization, researchers have been compelled to devise alternative strategies, such as the systemic delivery of OVA in the context of powerful adjuvants, which are alien to the way humans are exposed and sensitized to allergens. The objectives of these studies were to investigate immune-inflammatory responses to intranasal delivery of a purified house dust mite (HDM) extract and to evaluate the role of GM-CSF in this process. HDM was delivered to BALB/c mice daily for 10 days. After the last exposure, mice were killed, bronchoalveolar lavage was performed, and samples were obtained. Expression/production of Th2-associated molecules in the lymph nodes, lung, and spleen were evaluated by real-time quantitative PCR and ELISA, respectively. Using this exposure protocol, exposure to HDM alone generated Th2 sensitization based on the expression/production of Th2 effector molecules and airway eosinophilic inflammation. Flow cytometric analysis demonstrated expansion and activation of APCs in the lung and an influx of activated Th2 effector cells. Moreover, this inflammation was accompanied by airways hyper-responsiveness and a robust memory-driven immune response. Finally, administration of anti-GM-CSF-neutralizing Abs markedly reduced immune-inflammatory responses in both lung and spleen. Thus, intranasal delivery of HDM results in Th2 sensitization and airway eosinophilic inflammation that appear to be mediated, at least in part, by endogenous GM-CSF production.

Hyperpolarized (HP) 3helium (3He) dynamic MRI was used to investigate airway response in rats following intravenous (i.v.) bolus administration of a contractile agent, methacholine (MCh). The method provides direct visualization of the ventilated regions within the lung. Heterogeneous bronchoconstriction following the i.v. MCh injection was evident using this technique. These 3He dynamic lung images revealed that the inspired fresh air was shunted to the less-constricted regions after the MCh challenge in a similar manner as described by Laplace's relationship for the stability between adjacent alveoli. The airways in the more-constricted regions became nearly closed, resulting in air trapping, while the airways in the less-constricted regions remained effectively open, leading to overinflation. These data suggest a lung model of airway constriction partitioned into ventilated and nonventilated regions. These nonventilated regions are heterogeneously distributed in the lung and this distribution cannot be deduced from spirometric measurement of the whole lung. We demonstrate that a combination of functional 3He images and anatomical 1H images provide an effective method to diagnose regional lung abnormalities in rats.

T-cell-mediated airway inflammation is considered to be critical in the pathogenesis of airway hyperresponsiveness (AHR). We have described a mouse model in which chronic allergen exposure results in sustained AHR and aspects of airway remodeling and here sought to determine whether eliminating CD4(+) and CD8(+) cells, at a time when airway remodeling had occurred, would attenuate this sustained AHR. Sensitized BALB/c mice were subjected to either brief or chronic periods of allergen exposure and studied 24 h after brief or 4 wk after chronic allergen exposure. In both models, mice received three treatments with anti-CD4 and -CD8 monoclonal antibodies during the 10 days before outcome measurements. Outcomes included in vivo airway responsiveness to intravenous methacholine, CD4(+) and CD8(+) cell counts of lung and spleen using flow cytometric analysis, and airway morphometry using a computer-based image analysis system. Compared with saline control mice, brief allergen challenge resulted in AHR, which was eliminated by antibody treatment. Chronic allergen challenge resulted in sustained AHR and indexes of airway remodeling. This sustained AHR was not reversed by antibody treatment, even though CD4(+) and CD8(+) cells were absent in lung and spleen. These results indicate that T-cell-mediated inflammation is critical for development of AHR associated with brief allergen exposure, but is not necessary to maintain sustained AHR.

Studies of ventilator-associated lung injury in adult experimental animal models have documented that high tidal volume (TV) results in lung injury characterized by impaired compliance and dysfunctional surfactant. Yet, there is evidence that, in neonates, ventilation with a higher than physiologic TV leads to improved lung compliance. The purpose of our study was to evaluate how lung compliance and surfactant was altered by high TV ventilation in the neonate. We utilized a new model (mechanically air-ventilated newborn rats, 4-8 d old), and used 40 or 10 mL/kg TV strategies. Age-matched nonventilated animals served as controls. In all animals, dynamic compliance progressively increased after initiation of mechanical ventilation and was significantly greater than basal values after 60 min (p < 0.01). Lung lavage total surfactant with both TV strategies (p < 0.05) and the large aggregate fraction (only in TV = 40 mL/kg; p < 0.01) were significantly increased by 60 min of mechanical ventilation, compared with control animals. Ventilation with 40 mL/kg TV for 60 min adversely affected the lung surfactant surface-tension lowering properties (p < 0.01). After 180 min of ventilation with 40 mL/kg TV, the lung total surfactant content and dynamic compliance values were no longer distinct from the nonventilated animals' values. We conclude that, in the newborn rat, mechanical ventilation with a higher than physiologic TV increases alveolar surfactant content and, over time, alters its biophysical properties, thus promoting an initial but transient improvement in lung compliance.

Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge (P < 0.01) and exhibited marked eosinophilia and lymphocytosis in bronchoalveolar lavage fluids as well as significant pathological alterations in laryngotracheal histology compared with nonsensitized mice. We suggest that this approach will provide useful and necessary information on pulmonary mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function.

We investigated the effect of high VT ventilation on adult and newborn rats by examining pulmonary injury and cytokine messenger RNA (mRNA). On the basis of compliance, edema formation, and histology, ventilation with 25 ml.kg(-1) was more injurious to adult rats than newborns. Ventilation with 40 ml kg(-1) minimally affected compliance in newborns but caused death in adults. Ventilation of adults for 30 minutes at 25 ml kg(-1) upregulated the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and IL-10, whereas in newborns such ventilation only increased mRNA expression of MIP-2 and IL-10. When VT was raised to 40 ml kg(-1) in newborns, IL-1beta mRNA levels were additionally increased at 30 minutes, whereas ventilation for 3 hours additionally increased IL-6 and TNF-alpha mRNA. In newborns, the addition of 100% oxygen (O(2)) to 30 minutes of ventilation blunted the high VT induction of IL-1beta, IL-10, and MIP-2 mRNA expressions, whereas at 3 hours, 100% O(2) concentration synergistically increased the mRNAs for TNF-alpha and IL-6. Overall, adult rats are more susceptible to high VT-induced lung injury compared with newborns. In newborns, the inflammatory response is dependent on VT, duration, and supplemental O(2). Thus, recommendations for VT limitation based on adult data may be inappropriate for newborns.

BACKGROUND: Sudden, severe airway injury has been associated with an acute, and at times persisting, airway hyper-responsiveness with clinical features of asthma, termed reactive airways dysfunction syndrome (RADS). An attempt was made to develop a rat model of RADS by exposing inbred Fischer rats to inhaled 8 N acetic acid for 2 mins (13 N inhalation was lethal). METHODS: Lung resistance (RL) and lung elastance (EL) were measured in 14 eight- to 10-week old male rats. Baseline responsiveness to methacholine was quantified by calculating the dose required for doubling of RL. The next day, the study group (n=11) was exposed to aerosolized acetic acid. Control animals (n=3) were similarly exposed to buffered saline solution. RESULTS: Acetic acid exposure resulted in a significant (P<0.02) increase in RL (by 80%) and EL (by 67%), lasting less than 10 mins postexposure, but no significant change in methacholine responsiveness at one day and seven days postexposure. CONCLUSIONS: Failure to induce persistent airway hyper-responsiveness may relate to the choice of animal, choice of irritant, or insufficient level or duration of exposure, or may reflect a lack of individual predisposing cofactors such as smoking or underlying asthmatic predisposition.

STUDY OBJECTIVES: The fractional concentration of exhaled nitric oxide (FENO) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the FENO fall following inhaled beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients. STUDY DESIGN: Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 microg/d of iBDP; period 3, 400 microg/D of iBDP; and period 4, 800 microg/d of iBDP. Spirometry, FENO, and provocative concentration of methacholine resulting in a 20% fall in FEV(1)(PC(20)) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 microg/d of iBDP for 14 days (period 2), washout on placebo treatment until the FENO was within 15% of baseline (period 3), and 200 microg/d of iBDP for 14 days (period 4). RESULTS: Study A: Mean FEV(1) rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV(1) rise compared to placebo treatment, but with no significant separation of doses using FEV(1). FENO geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb)(78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in FENO from placebo treatment, but with significant separation of only the 100-microg and 800-microg doses by FENO. Geometric mean (95% confidence limits) PC(20) rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC(20) from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC(20). Study B: FENO fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between FENO in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220). CONCLUSIONS: FENO was superior to FEV(1) and PC(20) in separating doses of iBDP. The fall in FENO after two identical administrations of iBDP separated by placebo washout was highly reproducible.

BACKGROUND: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy. METHODS: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain:(1) a straight P-t curve (constant compliance, minimal stress);(2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O. RESULTS: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found. CONCLUSIONS: The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.

OBJECTIVE: To test the hypothesis that the lung injury induced by certain mechanical ventilation strategies is associated with changes in the pulmonary surfactant system. DESIGN: Analysis of the pulmonary surfactant system from isolated rat lungs after one of four different ventilatory strategies. SETTING: A research laboratory at a university. SUBJECTS: A total of 45 Sprague-Dawley rats. INTERVENTIONS: Isolated lungs were randomized to either no ventilation (0-TIME) or to ventilation at 40 breaths/min in a humidified 37 degrees C chamber for either 30 mins or 120 mins with one of the following four strategies: a) control (CON, 7 mL/kg, 3 cm H2O positive end-expiratory pressure); b) medium volume, zero end-expiratory pressure (MVZP, 15 mL/kg, 0 cm H2O end-expiratory pressure); c) medium volume, high positive end-expiratory pressure (MVHP, 15 mL/kg, 9 cm H2O positive end-expiratory pressure); and d) high volume, zero end-expiratory pressure (HVZP, 40 mL/kg, 0 cm H2O end-expiratory pressure). MEASUREMENTS: Pressure-volume curves were determined before and after the ventilation period, after which the lungs were lavaged for surfactant analysis. MAIN RESULTS: Compared with 0-TIME, 30 mins of ventilation with the HVZP strategy or 120 mins of ventilation with CON and MVZP strategies caused a significant decrease in compliance. Groups showing a decreased compliance had significant increases in the amount of surfactant, surfactant large aggregates, and total lavage protein compared with 0-TIME. CONCLUSIONS: A short period of injurious mechanical ventilation can cause a decrease in lung compliance that is associated with a large influx of proteins into the alveolar space and with alterations of the pulmonary surfactant system. The changes of surfactant in these experiments are different from those seen in acute lung injury, indicating that they may represent an initial response to mechanical ventilation.

OBJECTIVE: To examine the hypothesis that partial liquid ventilation (PLV) with perfluorocarbon would decrease serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model. DESIGN: Prospective, controlled animal study. SETTINGS: Research laboratory in a university setting. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Treatment with intratracheal perflubron or control mechanical ventilation beginning 30 mins after acid aspiration. MEASUREMENTS AND MAIN RESULTS: PLV with perfluorocarbon compared with control ventilation resulted in significantly greater mean arterial blood pressures at 3 and 4 hrs and greater arterial Po2 at all times. Serum tumor necrosis factor-alpha at 2, 3, and 4 hrs was significantly less than that observed in the control group (4-hr values: 80+/-64 pg/mL vs. 658+/-688 pg/mL; p<.05), although no significant difference in tracheal fluid tumor necrosis factor-alpha concentrations (1425+/-1347 pg/mL vs. 2219+/-1933 pg/mL) was found. CONCLUSION: We conclude that the effects of PLV with perfluorocarbon can extend beyond improvements in pulmonary physiology and that PLV may be beneficial in reducing systemic sequelae of acute lung injury and inflammation.

BACKGROUND: Allergy to pets, particularly cats, is one of the most important determinants of asthma and asthma-like symptoms in many parts of the world. Cat allergen is found in homes and public places without cats. OBJECTIVE: The purpose of the study is to investigate the prevalence of sensitization to cat on the island of Tristan da Cunha where cats have been eliminated since 1974. METHODS: A cross-sectional survey was conducted in 1993 on all residents on the island including allergy skin testing. Dust samples were collected from 20 homes on the island for measurement of house dust mite and cat allergens. RESULTS: Positive skin test reaction to cat was present in 57 (20.1%) of all islanders and in six (12.8%) of those born in or after 1975, 1 year after cats had been exterminated. Five of these six residents were born within 5 years of extermination of cats; two of these had attended school outside the island. A low level of cat allergen (Fel d 1) was found in only one out of 20 homes even though house dust mite allergens (Der p 1 or Der f 1) were found in all homes. CONCLUSION: Sensitization to cat allergen occurs on the island of Tristan da Cunha where there is no direct exposure to cats. This is due either to the persistence of the allergen after the removal of the animal or to the allergen being brought in on visitors' clothing.

Exhaled nitric oxide (ENO) is used increasingly as a surrogate marker of airway inflammation in research protocols that may incorporate standard efficacy measures, such as spirometry before and after bronchodilator, which could affect ENO measurements. In seven healthy volunteers and 11 mild asthmatic subjects, we measured ENO before and serially for 1 h after spirometry. On two additional days in the subjects with asthma, we reexamined the effect of spirometry as before, followed by the serial measurement of ENO for 1 h after two puffs of salbutamol (100 microgram/puff) by metered-dose inhaler or matching placebo. As early as 1 min after spirometry, ENO fell by 13% and 10% in the normal and asthmatic subjects, respectively. In both groups, ENO returned to baseline over 1 h. In the asthmatic subjects, salbutamol caused a significant mean increase of the order of 10 parts per billion in ENO (p < 0.001) for 1 h as compared with placebo inhaler. We conclude that spirometry and beta2-agonist may perturb ENO values and recommend that studies control for these factors.

Mechanical ventilation is an indispensable tool in the management of respiratory and ventilatory failure. However, ventilation per se may also initiate or exacerbate lung injury, contributing to patient morbidity and mortality. In this review, we examine the current mechanisms of ventilator-induced injury including those that primarily involve physical disruption of the lung, as well as those more recently described that involve cell- and inflammatory-mediator-induced injury. The latter have received attention of late because of the possible systemic sequelae such as multiple system organ failure, the primary cause of death of patients with acute respiratory distress syndrome. Although much remains to be elucidated about the mechanisms of ventilator-induced injury, it is hoped that novel approaches addressing both the physiologic as well as molecular effects of ventilation will lead to innovative therapeutic approaches that improve patient outcome.

Nitric oxide (NO) of endogenous origin is present in exhaled breath. An increase in exhaled NO concentration (ENO) has been described in bronchial asthma and ENO falls after inhaled steroid therapy. The sources of ENO may include pulmonary blood, the gas exchange region, conducting airways and the nasal cavity. In four healthy volunteers, a catheter was placed in a main bronchus after topical anesthesia in order to sample airway NO (CNO). Exhaled nitric oxide of bronchopulmonary and oropharyngeal origin (ENO(b/o)) was measured while excluding nasal NO and was controlled for expiratory flow. During the same exhalation, ENO(b/o) was compared to CNO at multiple sites in the airway as the catheter was progressively withdrawn. Mean CNO concentration in a position corresponding to a main bronchus was 51.4 +/- 10.8% of ENO(b/o). As the catheter was withdrawn, mean CNO concentration progressively increased both in absolute values and as a proportion of ENO(b/o), until in the oropharynx, it was 96.1 +/- 5.2% ENO(b/o). We conclude that a significant proportion of ENO(b/o) arises in the large airways and trachea in normal subjects and contains a minor oropharyngeal component.

The measurement of exhaled nitric oxide (ENO) is recognized as a marker of airway inflammation. ENO was measured in 10 nonsteroid-treated asthmatics at recruitment, during 3 weeks of inhaled beclomethasone (1000 microg/day) and for 3 weeks after withdrawal. Baseline ENO was increased in asthma compared with nonasthmatics (85.0+/-54.5 vs. 24.5+/-14.8 ppb, p < 0.0001). After inhaled steroid, there was no significant change in forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC), but methacholine PC20 rose significantly (p = 0.0345). ENO (mean+/-SD;% baseline) fell after 1 week on steroid to 60.6+/-31.1 and rose to 95.3+/-46.1 at 1 week after withdrawal. ENO did not correlate with PC20 or FEV1. The changes in ENO and PC20 were inversely correlated (r2 = 0.325). ENO may be an index of airway inflammation and therapeutic response in bronchial asthma.

This is a report on a methodological adaptation of the photogrammetric technique, which is used in other medical specialties, for use in analyzing respiratory movements. Photogrammetry and a model of photogrammetry designated biofotogrametria para análise da mecânica respiratória (BAMER, photogrammetric analysis of respiratory mechanics) were tested under previously described pathophysiological conditions: post-exercise dynamic hyperinflation using positive end-expiratory pressure. The BAMER model identified an increase in the thoraco-abdominal area following exercise using positive end-expiratory pressure. These results are comparable to those obtained with more robust systems of respiratory kinematics. The use of photogrammetry has value in many areas, since it produces quantitative data, being particularly relevant in pediatrics, in which monitoring resources are scarce.

Many chronic human lung diseases have their origin in early childhood yet most murine models used to study them utilize adult mice. An important component of the asthma phenotype is exaggerated airway responses, frequently modelled by methacholine (MCh) challenge. The present study was undertaken to characterize MCh responses in mice from 2 to 8 weeks of age measuring absolute lung volume and volume-corrected respiratory mechanics as outcome variables. Female BALB/c mice aged 2, 3, 4, 6 & 8 weeks were studied during cumulative intravenous MCh challenge. Following each MCh dose absolute lung volume was measured plethysmographically at functional residual volume (FRC) and during a slow inflation to 20 hPa transrespiratory pressure. Respiratory system impedance (Zrs) was measured continuously during the inflation manoeuvre and partitioned into airway and constant phase parenchymal components by model fitting. Volume-corrected (specific) estimates of respiratory mechanics were calculated. Intravenous MCh challenge induced a predominantly airway response with no evidence of airway closure in any age group. No changes in FRC were seen in mice of any age during the MCh challenge. The specific airway resistance MCh dose response curves did not show significant differences between the age groups. The results from the present study do not show systematic differences in MCh responsiveness in mice from 2 to 8 weeks of age. Key words: Animal Models, Respiratory Impedance, Lung Volumes.

There are invasive and noninvasive pulmonary function tests available which are sensitive in detecting bronchoconstriction in rodents. Noninvasively measured midexpiratory flow (EF(50)) has been shown to be an appropriate parameter to monitor bronchoconstriction in a large number of animals, e.g. for screening purposes. Recently, a novel technique for repetitive lung function measurements in orotracheally intubated, spontaneously breathing mice has been established. Bronchoconstriction is assessed by the "gold standard" parameters airway resistance and dynamic compliance in response to aerosolized methacholine or allergens in anesthetized mice. This measurement technique has been combined with an inhalation technique which has been optimized to allow simultaneous lung function measurement in intubated animals and to obtain high aerosol concentrations. A feedback dose control system has been developed to administer a defined and constant aerosol dose to each individual animal. Using this system a prominent early allergic response and late airway hyperresponsiveness could be demonstrated in intubated mice challenged with Aspergillus fumigatus allergen. We conclude: The noninvasive EF(50) method seems particularly appropriate for measurements of respiratory function in large numbers of conscious mice in assembly line fashion. The invasive technology - newly established for the mouse - is more sensitive and specific since true airway resistance and dynamic compliance are determined and allows now the adequate detection of an early allergic response in the mouse and also repetitive measurements e.g. to assess the airway hyperresponsiveness in the same animal or for monitoring purposes in chronic models.

Ventilator performance can be tied to the individual systems that control delivery of pressure, volume, and flow. Clinician's need not be engineers but should understand how individual device mechanics and algorithms can affect patient ventilator synchrony.

The barometric method has recently been employed to detect airway constriction in small animals. This study was designed to evaluate the barometric method to detect mediator-induced central and peripheral airway constriction in BALB/c mice. First, the central airway constrictor carbachol and the peripheral airway constrictor histamine were employed to induce airway constriction, which was detected by both the conventional body plethysmography and the barometric method in anesthetized mice. Second, bronchoconstriction induced by aerosolized carbachol or other mediators was detected with the barometric plethysmography in conscious, unrestrained mice. Carbachol inhalation caused about four-fold increase in pulmonary resistance (RL) and about two-fold increase in enhanced pause (Penh) in anesthetized mice. In contrast, in the same preparation, histamine aerosol induced a decrease in dynamic compliance (Cdyn), with no alteration in RL or Penh. In awake mice, carbachol and methacholine caused increases in Penh, frequency, and tidal volume (VT). On the other hand, histamine, histamine + bradykinin, and prostaglandin-D2 did not alter Penh but decreased VT in conscious mice. These data suggest that there was no sufficient evidence to indicate that Penh could be a good indicator of bronchoconstriction for the whole airways.

Ventilator-associated pneumonia results from bacterial colonisation of the aerodigestive tract or aspiration of contaminated secretions into the lower airways. As a consequence of infection of the lung parenchyma and alveolitis, accumulation of inflammatory exudates and infiltration of airway mucosa can lead to unfavourable respiratory mechanics in ventilator-associated pneumonia. Tracheal suction is often employed by nursing staff in the management of mechanically ventilated patients with ventilator-associated pneumonia but this technique has the potential to increase respiratory resistance. Manual hyperinflation is used by physiotherapists to improve lung volume and mobilise secretions and has been shown to increase lung compliance. The effect of manual hyperinflation on airway resistance has not been studied. This study aims to demonstrate an additional mechanical benefit to the respiratory system when manual hyperinflation and suction techniques are combined, by comparing the application of manual hyperinflation and suction with suction alone on static lung compliance (C(L)) and inspiratory resistance (R(AW)) in mechanically ventilated patients with ventilator-associated pneumonia. Fifteen adult patients with ventilator-associated pneumonia were recruited and acted as their own controls. Manual hyperinflation followed by suction (manual hyperinflation plus suction) and suction alone were applied consecutively, in random order, on two occasions, four hours apart. Respiratory variables, C(L) and R(AW), were measured five times and the averaged value documented. Data were recorded before, immediately after, and 30 minutes after each intervention protocol. C(L) increased by 22% and R(AW) decreased by 21%, up to 30 minutes after manual hyperinflation plus suction, but not after suction alone. This study suggests that manual hyperinflation in conjunction with suction induces beneficial changes in respiratory mechanics in mechanically ventilated patients with ventilator-associated pneumonia.

STUDY OBJECTIVE: To compare the effect of inspiratory time and lung compliance on tidal volume (Vt) delivery in anesthesia and intensive care unit (ICU) ventilators operating in pressure control mode. SETTING: Respiratory research laboratory of a tertiary care medical center. DESIGN: Two anesthesia ventilators with pressure control capability (Narkomed 6000, Drager Medical, Inc, Telford, Pa, and the Datex-Ohmeda Aestiva 5, Datex-Ohmeda, Inc, Madison, Wis) and one critical care ventilator (Puritan Bennett 7200, Puritan-Bennett, Pleasanton, Calif) were studied under varying inspiratory time and lung compliance conditions using a mechanical lung model. INTERVENTION: Each ventilator was set to pressure control mode at a fixed inspiratory/expiratory (I/E) ratio. The respiratory rate (RR) was varied between 6 and 28 breaths per minute. Lung compliance and inspiratory time settings were set to simulate clinical conditions known to affect anesthesia ventilator performance. MEASUREMENTS: Inspiratory flow, Vts, and peak airway pressures were measured using the on-board monitor for each ventilator, and confirmed with the Bicore CP-100 pulmonary mechanics monitor (Bicore Monitoring Systems, Inc, Irvine, Calif). To assess differences in inspiratory flow between ventilators, airway pressures were continuously monitored during inspiration. MAIN RESULTS: Increasing RRs caused delivered Vts to decrease for all ventilators. However, decreases in Vts were significantly larger for anesthesia than for ICU ventilators. At a lung compliance of 0.02 L/cm H(2)O and set Vt of 700 mL, Vt delivery for the Puritan Bennett 7200 ventilator remained at 88% of baseline, but decreased to 76% for the Aestiva 5 when RRs were increased from 6 to 28 breaths per minute (P <.0025). Airway pressure tracings demonstrated a slower increase in inspiratory airway pressure for the Aestiva 5 than for the other ventilators. CONCLUSION: Differences in inspiratory flow delivery between ICU and anesthesia ventilators can cause differences in Vt delivery when the pressure control mode is used at high RRs. These differences can significantly impact the perioperative care of critically ill patients requiring ventilatory support.

Obstruction of the large and small airways occurs in several diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, and bronchiolitis. This article discusses the role of ventilator waveforms in the context of factors that contribute to the development of respiratory failure and acute respiratory distress in patients with obstructive lung disease. Displays of pressure, flow, and volume, flow-volume loops, and pressure-volume loops are available on most modern ventilators. In mechanically ventilated patients with airway obstruction, ventilator graphics aid in recognizing abnormalities in function, in optimizing ventilator settings to promote patient-ventilator interaction, and in diagnosing complications before overt clinical signs develop. Ventilator waveforms are employed to detect the presence of dynamic hyperinflation and to measure lung mechanics. Various forms of patient-ventilator asynchrony (eg, auto-triggering and delayed or ineffective triggering) can also be detected by waveform analysis. Presence of flow limitation during expiration and excessive airway secretions can be determined from flow-volume loops. Abnormalities in pressure-volume loops occur when the trigger sensitivity is inadequate, with alterations in respiratory compliance, or during patient-ventilator asynchrony. Thus, ventilator waveforms play an important role in management of mechanically-ventilated patients with obstructive lung disease.