Assessment of dynamic mechanical properties of the respiratory system during high-frequency oscillatory ventilation*.

OBJECTIVES: 1) To investigate the possibility of estimating respiratory system impedance (Zrs, forced oscillation technique) by using high-amplitude pressure oscillations delivered during high-frequency oscillatory ventilation; 2) to characterize the relationship between Zrs and continuous distending pressure during an increasing/decreasing continuous distending pressure trial; 3) to evaluate how the optimal continuous distending pressure identified by Zrs relates to the point of maximal curvature of the deflation limb of the quasi-static pressure-volume curve. DESIGN: Prospective laboratory animal investigation. SETTING: Experimental medicine laboratory. SUBJECTS: Eight New Zealand rabbits. INTERVENTIONS: The rabbits were ventilated with high-frequency oscillatory ventilation. Zrs was measured while continuous distending pressure was increased and decreased between 2 and 26 cm H2O in 1-minute steps of 4 cm H2O. At each step, a low-amplitude (6 cm H2O) sinusoidal signal was alternated with a high-amplitude (18 cm H2O) asymmetric high-frequency oscillatory ventilation square pressure waveform. Pressure-volume curves were determined at the end of the continuous distending pressure trial. All measurements were repeated after bronchoalveolar lavage. MEASUREMENTS AND MAIN RESULTS: Zrs was estimated from flow and pressure measured at the inlet of the tracheal tube and expressed as resistance (Rrs) and reactance (Xrs). Linear correlation between the values, measured by applying the small-amplitude sinusoidal signal and the ventilator waveform, was good for Xrs (r = 0.95 ± 0.04) but not for Rrs (r = 0.60 ± 0.34). Following lavage, the Xrs-continuous distending pressure curves presented a maximum on the deflation limb, identifying an optimal continuous distending pressure that was, on average, 1.1 ± 1.7 cm H2O below the point of maximal curvature of the deflation limb of the pressure-volume curves. CONCLUSIONS: Xrs can be accurately measured during high-frequency oscillatory ventilation without interrupting ventilation and/or connecting additional devices. An optimal continuous distending pressure close to the point of maximal curvature of the deflation limb of quasi-static pressure-volume curve can be identified by measuring Zrs during a decreasing continuous distending pressure trial. Zrs might constitute a useful bedside tool for monitoring lung mechanics and improving the continuous distending pressure optimization during high-frequency oscillatory ventilation.

Optimizing positive end-expiratory pressure by oscillatory mechanics minimizes tidal recruitment and distension: an experimental study in a lavage model of lung injury.

INTRODUCTION: It is well established that during mechanical ventilation of patients with acute respiratory distress syndrome cyclic recruitment/derecruitment and overdistension are potentially injurious for lung tissues. We evaluated whether the forced oscillation technique (FOT) could be used to guide the ventilator settings in order to minimize cyclic lung recruitment/derecruitment and cyclic mechanical stress in an experimental model of acute lung injury. METHODS: We studied six pigs in which lung injury was induced by bronchoalveolar lavage. The animals were ventilated with a tidal volume of 6 ml/kg. Forced oscillations at 5 Hz were superimposed on the ventilation waveform. Pressure and flow were measured at the tip and at the inlet of the endotracheal tube respectively. Respiratory system reactance (Xrs) was computed from the pressure and flow signals and expressed in terms of oscillatory elastance (EX5). Positive end-expiratory pressure (PEEP) was increased from 0 to 24 cm H2O in steps of 4 cm H2O and subsequently decreased from 24 to 0 in steps of 2 cm H2O. At each PEEP step CT scans and EX5 were assessed at end-expiration and end-inspiration. RESULTS: During deflation the relationship between both end-expiratory and end-inspiratory EX5 and PEEP was a U-shaped curve with minimum values at PEEP = 13.4 ± 1.0 cm H2O (mean ± SD) and 13.0 ± 1.0 cm H2O respectively. EX5 was always higher at end-inspiration than at end-expiration, the difference between the average curves being minimal at 12 cm H2O. At this PEEP level, CT did not show any substantial sign of intra-tidal recruitment/derecruitment or expiratory lung collapse. CONCLUSIONS: Using FOT it was possible to measure EX5 both at end-expiration and at end-inspiration. The optimal PEEP strategy based on end-expiratory EX5 minimized intra-tidal recruitment/derecruitment as assessed by CT, and the concurrent attenuation of intra-tidal variations of EX5 suggests that it may also minimize tidal mechanical stress.

Positive end-expiratory pressure optimization with forced oscillation technique reduces ventilator induced lung injury: a controlled experimental study in pigs with saline lavage lung injury.

INTRODUCTION: Protocols using high levels of positive end-expiratory pressure (PEEP) in combination with low tidal volumes have been shown to reduce mortality in patients with severe acute respiratory distress syndrome (ARDS). However, the optimal method for setting PEEP is yet to be defined. It has been shown that respiratory system reactance (Xrs), measured by the forced oscillation technique (FOT) at 5 Hz, may be used to identify the minimal PEEP level required to maintain lung recruitment. The aim of the present study was to evaluate if using Xrs for setting PEEP would improve lung mechanics and reduce lung injury compared to an oxygenation-based approach. METHODS: 17 pigs, in which acute lung injury (ALI) was induced by saline lavage, were studied. Animals were randomized into two groups: in the first PEEP was titrated according to Xrs (FOT group), in the control group PEEP was set according to the ARDSNet protocol (ARDSNet group). The duration of the trial was 12 hours. In both groups recruitment maneuvers (RM) were performed every 2 hours, increasing PEEP to 20 cmH2O. In the FOT group PEEP was titrated by monitoring Xrs while PEEP was reduced from 20 cmH2O in steps of 2 cmH2O. PEEP was considered optimal at the step before which Xrs started to decrease. Ventilatory parameters, lung mechanics, blood gases and hemodynamic parameters were recorded hourly. Lung injury was evaluated by histopathological analysis. RESULTS: The PEEP levels set in the FOT group were significantly higher compared to those set in the ARDSNet group during the whole trial. These higher values of PEEP resulted in improved lung mechanics, reduced driving pressure, improved oxygenation, with a trend for higher PaCO2 and lower systemic and pulmonary pressure. After 12 hours of ventilation, histopathological analysis showed a significantly lower score of lung injury in the FOT group compared to the ARDSNet group. CONCLUSIONS: In a lavage model of lung injury a PEEP optimization strategy based on maximizing Xrs attenuated the signs of ventilator induced lung injury. The respiratory system reactance measured by FOT could thus be an important component in a strategy for delivering protective ventilation to patients with ARDS/acute lung injury.

Measurement of total and compartmental lung volume changes in newborns by optoelectronic plethysmography.

The study of respiratory mechanics in infants requires a noninvasive accurate measurement of the lung volume changes (DeltaVL). Optoelectronic plethysmography (OEP) allows the assessment of DeltaVL through the measurement of the chest wall surface motion and it has been proved to be accurate in adults. The aim of this study was to apply OEP to newborns and to validate it by comparison to pneumotachography. Twenty term and preterm newborns (GA = 34 +/- 5 wk) in stable condition were studied during 1 to 2 min periods of quiet breathing in supine position. Airway opening flow was measured by applying a facemask connected to a pneumotachograph (PNT) and integrated to provide the DeltaVL. Chest wall volume changes were simultaneously measured by OEP. The tidal volume values measured by pneumotachography and by OEP were compared for each breath. A total of 771 breaths from all patients were considered. Bland-Altmann analysis showed a mean difference of -0.08 mL and a limit of agreement ranging from -2.98 to 2.83 mL. Linear regression analysis demonstrated good correlation between the two techniques (r = 0.95, q = 1.00 mL, m = 0.96). OEP provides accurate measurements of DeltaVL in newborns and may be useful to study respiratory mechanics and breathing patterns during spontaneous breathing and mechanical ventilation.

Changes in the mechanical properties of the respiratory system during the development of interstitial lung edema.

BACKGROUND: Pulmonary edema induces changes in airway and lung tissues mechanical properties that can be measured by low-frequency forced oscillation technique (FOT). It is preceded by interstitial edema which is characterized by the accumulation of extravascular fluid in the interstitial space of the air-blood barrier. Our aim was to investigate the impact of the early stages of the development of interstitial edema on the mechanical properties of the respiratory system. METHODS: We studied 17 paralysed and mechanically ventilated closed-chest rats (325-375 g). Total input respiratory system impedance (Zrs) was derived from tracheal flow and pressure signals by applying forced oscillations with frequency components from 0.16 to 18.44 Hz distributed in two forcing signals. In 8 animals interstitial lung edema was induced by intravenous infusion of saline solution (0.75 ml/kg/min) for 4 hours; 9 control animals were studied with the same protocol but without infusion. Zrs was measured at the beginning and every 15 min until the end of the experiment. RESULTS: In the treated group the lung wet-to-dry weight ratio increased from 4.3 +/- 0.72 to 5.23 +/- 0.59, with no histological signs of alveolar flooding. Resistance (Rrs) increased in both groups over time, but to a greater extent in the treated group. Reactance (Xrs) did not change in the control group, while it decreased significantly at all frequencies but one in the treated. Significant changes in Rrs and Xrs were observed starting after ~135 min from the beginning of the infusion. By applying a constant phase model to partition airways and tissue mechanical properties, we observed a mild increase in airways resistance in both groups. A greater and significant increase in tissue damping (from 603.5 +/- 100.3 to 714.5 +/- 81.9 cmH2O/L) and elastance (from 4160.2 +/- 462.6 to 5018.2 +/- 622.5 cmH2O/L) was found only in the treated group. CONCLUSION: These results suggest that interstitial edema has a small but significant impact on the mechanical features of lung tissues and that these changes begin at very early stages, before the beginning of accumulation of extravascular fluid into the alveoli.

Benefits of six degrees of freedom for optically driven patient set-up correction in SBRT.

To quantify the advantages of a 6 degrees of freedom (dof) versus the conventional 3- or 4-dof correction modality for stereotactic body radiation therapy (SBRT) treatments. Eighty-five patients were fitted with 5-7 infra-red passive markers for optical localization. Data, acquired during the treatment, were analyzed retrospectively to simulate and evaluate the best approach for correcting patient misalignments. After the implementation of each correction, the new position of the target (tumor's center of mass) was estimated by means of a dedicated stereotactic algorithm. The Euclidean distance between the corrected and the planned location of target point was calculated and compared to the initial mismatching. Initial and after correction median+/-quartile displacements affecting external control points were 3.74+/-2.55 mm (initial), 2.45+/-0.91 mm (3-dof), 2.37+/-0.95 mm (4-dof), and 2.03+/-1.47 mm (6-dof). The benefit of a six-parameter adjustment was particularly evident when evaluating the results relative to the target position before and after the re-alignment. In this context, the Euclidean distance between the planned and the current target point turned to 0.82+/-1.12 mm (median+/-quartile values) after the roto-translation versus the initial displacement of 2.98+/-2.32 mm. No statistical improvements were found after 3- and 4-dof correction (2.73+/-1.22 mm and 2.60+/-1.31 mm, respectively). Angular errors were 0.09+/-0.93 degrees (mean+/-std). Pitch rotation in abdomen site showed the most relevant deviation, being -0.46+/-1.27 degrees with a peak value of 5.46 degrees . Translational misalignments were -0.68+/-2.60 mm (mean+/-std) with the maximum value of 12 mm along the cranio-caudal direction. We conclude that positioning system platforms featuring 6-dof are preferred for high precision radiation therapy. Data are in line with previous results relative to other sites and represent a relevant record in the framework of SBRT.

3D optoelectronic analysis of interfractional patient setup variability in frameless extracranial stereotactic radiotherapy.

PURPOSE: To investigate size and frequency of interfractional patient setup variability in hypofractionated stereotactic extracranial radiotherapy. METHODS AND MATERIALS: Infrared optical 3D tracking of surface markers was applied to quantify setup variability on 51 patients. Isocenter position repeatability was assessed by means of frameless anatomic calibration and was compared with portal image evaluation. Specific data analysis allowed for compensation of patients' breathing movements and for separation of the effects of operator-dependent misalignments and respiration-induced displacements. Effects of patient position (supine vs. prone) and treatment table configuration were investigated. RESULTS: Patient positioning assisted by the optical tracking device allowed reducing displacements of surface control points within the 3-mm range. Errors in isocenter localization were in the range of a few millimeters. This was in agreement with the portal image evaluation. Breathing motion introduced appreciable errors, which increased control points and isocenter 3D variability. This effect was significantly higher than those related to other investigated factors. CONCLUSIONS: The role of infrared optical tracking devices for patient positioning is assessed on a large patient population. Their use in the frame of high-precision radiotherapy is emphasized by the application of related methodologies for breathing phase detection and frameless isocenter localization.

Patient set-up verification by infrared optical localization and body surface sensing in breast radiation therapy.

BACKGROUND AND PURPOSE: The aim of the study was to investigate the clinical application of a technique for patient set-up verification in breast cancer radiotherapy, based on the 3D localization of a hybrid configuration of surface control points. MATERIALS AND METHODS: An infrared optical tracker provided the 3D position of two passive markers and 10 laser spots placed around and within the irradiation field on nine patients. A fast iterative constrained minimization procedure was applied to detect and compensate patient set-up errors, through the control points registration with reference data coming from treatment plan (markers reference position, CT-based surface model). RESULTS: The application of the corrective spatial transformation estimated by the registration procedure led to significant improvement of patient set-up. Median value of 3D errors affecting three additional verification markers within the irradiation field decreased from 5.7 to 3.5 mm. Errors variability (25-75%) decreased from 3.2 to 2.1 mm. Laser spots registration on the reference surface model was documented to contribute substantially to set-up errors compensation. CONCLUSIONS: Patient set-up verification through a hybrid set of control points and constrained surface minimization algorithm was confirmed to be feasible in clinical practice and to provide valuable information for the improvement of the quality of patient set-up, with minimal requirement of operator-dependant procedures. The technique combines conveniently the advantages of passive markers based methods and surface registration techniques, by featuring immediate and robust estimation of the set-up accuracy from a redundant dataset.

Robust frameless stereotactic localization in extra-cranial radiotherapy.

In the field of extra-cranial radiotherapy, several inaccuracies can make the application of frameless stereotactic localization techniques error-prone. When optical tracking systems based on surface fiducials are used, inter- and intra-fractional uncertainties in marker three-dimensional (3D) detection may lead to inexact tumor position estimation, resulting in erroneous patient setup. This is due to the fact that external fiducials misdetection results in deformation effects that are poorly handled in a rigid-body approach. In this work, the performance of two frameless stereotactic localization algorithms for 3D tumor position reconstruction in extra-cranial radiotherapy has been specifically tested. Two strategies, unweighted versus weighted, for stereotactic tumor localization were examined by exploiting data coming from 46 patients treated for extra-cranial lesions. Measured isocenter displacements and rotations were combined to define isocentric procedures, featuring 6 degrees of freedom, for correcting patient alignment (isocentric positioning correction). The sensitivity of the algorithms to uncertainties in the 3D localization of fiducials was investigated by means of 184 numerical simulations. The performance of the implemented isocentric positioning correction was compared to conventional point-based registration. The isocentric positioning correction algorithm was tested on a clinical dataset of inter-fractional and intra-fractional setup errors, which was collected by means of an optical tracker on the same group of patients. The weighted strategy exhibited a lower sensitivity to fiducial localization errors in simulated misalignments than those of the unweighted strategy. Isocenter 3D displacements provided by the weighted strategy were consistently smaller than those featured by the unweighted strategy. The peak decrease in median and quartile values of isocenter 3D displacements were 1.4 and 2.7 mm, respectively. Concerning clinical data, the weighted strategy isocentric positioning correction provided the reduction of fiducial registration errors, featuring up to 61.7% decrease in median values (versus 46.8% for the unweighted strategy) of initial displacements. The weighted strategy proved high performance in minimizing the effects of fiducial localization errors, showing a great potential in improving patient setup. The clinical data analysis revealed that the application of a robust reconstruction algorithm may provide high-quality results in patient setup verification, by properly managing external fiducials localization errors.

Chest wall mechanics during pressure support ventilation.

INTRODUCTION: During pressure support ventilation (PSV) a part of the breathing pattern is controlled by the patient, and synchronization of respiratory muscle action and the resulting chest wall kinematics is a valid indicator of the patient's adaptation to the ventilator. The aim of the present study was to analyze the effects of different PSV settings on ventilatory pattern, total and compartmental chest wall kinematics and dynamics, muscle pressures and work of breathing in patients with acute lung injury. METHOD: In nine patients four different levels of PSV (5, 10, 15 and 25 cmH2O) were randomly applied with the same level of positive end-expiratory pressure (10 cmH2O). Flow, airway opening, and oesophageal and gastric pressures were measured, and volume variations for the entire chest wall, the ribcage and abdominal compartments were recorded by opto-electronic plethysmography. The pressure and the work generated by the diaphragm, rib cage and abdominal muscles were determined using dynamic pressure-volume loops in the various phases of each respiratory cycle: pre-triggering, post-triggering with the patient's effort combining with the action of the ventilator, pressurization and expiration. The complete breathing pattern was measured and correlated with chest wall kinematics and dynamics. RESULTS: At the various levels of pressure support applied, minute ventilation was constant, with large variations in breathing frequency/ tidal volume ratio. At pressure support levels below 15 cmH2O the following increased: the pressure developed by the inspiratory muscles, the contribution of the rib cage compartment to the total tidal volume, the phase shift between rib cage and abdominal compartments, the post-inspiratory action of the inspiratory rib cage muscles, and the expiratory muscle activity. CONCLUSION: During PSV, the ventilatory pattern is very different at different levels of pressure support; in patients with acute lung injury pressure support greater than 10 cmH2O permits homogeneous recruitment of respiratory muscles, with resulting synchronous thoraco-abdominal expansion.

Inverse dynamic investigation of voluntary leg lateral movements in weightlessness: a new microgravity-specific strategy.

This study deals with the quantitative assessment of exchanged forces and torques at the restraint point during whole body posture perturbation movements in long-term microgravity. The work was based on the results of a previous study focused on trunk bending protocol, which suggested that the minimization of the torques exchanged at the restraint point could be a strategy for movement planning in microgravity (J. Biomech. 36(11) (2003) 1691). Torques minimization would lead to the optimization of muscles activity, to the minimization of energy expenditure and, ultimately, to higher movement control capabilities. Here, we focus on leg lateral abduction from anchored stance. The analysis was based on inverse dynamic modelling, leading to the estimation of the total angular momentum at the supporting ankle joint. Results agree with those obtained for trunk bending movements and point out a consistent minimization of the torques exchanged at the restraint point in weightlessness. Given the kinematic features of the examined motor task, this strategy was interpreted as a way to master the rotational dynamic effects on the frontal plane produced by leg lateral abduction. This postural stabilizing effects was the result of a multi-segmental compensation strategy, consisting of the counter rotation of the supporting limb and trunk accompanying the leg raising. The observed consistency of movement-posture co-ordination patterns among lateral leg raising and trunk bending is put forward as a novel interpretative issue of the adaptation mechanisms of the motor system to sustained microgravity, especially if one considers the completely different kinematics of the centre of mass, which was observed in weightlessness for these two motor tasks.

Redundant system of passive markers for ultrasound scanhead tracking.

Scanhead tracking by opto-electronic (OE) systems allows high accuracy in three-dimensional (3-D) freehand ultrasound imaging. In this paper, a new set of methods is proposed and compared with the standard approach [Gram-Schmidt method (GS)]. Three redundancy-based algorithms are introduced to compensate for possible loss of markers during data acquisition: regression plane (RP), multiple Gram-Schmidt (MGS), and center of mass least square (CMLS). When combined with the ultrasound instrument, the root-mean-squared (RMS) uncertainty in locating target points, over a working volume of 420 mm x 490 mm x 100 mm, improved by 7% and 24% using MGS and CMLS method respectively, compared to GS. A lower improvement was obtained with RP methods (5%), using the best marker configuration. In conclusion, CMLS method provides a robust and accurate procedure for 3-D freehand ultrasound scanhead tracking, able to manage possible loss of markers, with interesting perspectives for image fusion and body referenced 3-D ultrasound.

Moving Along: In biomechanics, rehabilitation engineering, and movement analysis, Italian researchers are making great strides.

In Italy, biomechanics research and the analysis of human and animal movement have had a very long history, beginning with the exceptional pioneering work of Leonardo da Vinci. In 1489, da Vinci began investigating human anatomy, including an examination of human tendons, muscles, and the skeletal system. He continued this line of inquiry later in life, identifying what he called "the four powers--movement, weight, force, and percussion"--and how he thought they worked in the human body. His approach, by the way, was very modern--analyzing nature through anatomy, developing models for interpretation, and transferring this knowledge to bio-inspired machines.

Correlated variability in the breathing pattern and end-expiratory lung volumes in conscious humans.

In order to characterize the variability and correlation properties of spontaneous breathing in humans, the breathing pattern of 16 seated healthy subjects was studied during 40 min of quiet breathing using opto-electronic plethysmography, a contactless technology that measures total and compartmental chest wall volumes without interfering with the subjects breathing. From these signals, tidal volume (VT), respiratory time (TTOT) and the other breathing pattern parameters were computed breath-by-breath together with the end-expiratory total and compartmental (pulmonary rib cage and abdomen) chest wall volume changes. The correlation properties of these variables were quantified by detrended fluctuation analysis, computing the scaling exponenta. VT, TTOT and the other breathing pattern variables showed α values between 0.60 (for minute ventilation) to 0.71 (for respiratory rate), all significantly lower than the ones obtained for end-expiratory volumes, that ranged between 1.05 (for rib cage) and 1.13 (for abdomen) with no significant differences between compartments. The much stronger long-range correlations of the end expiratory volumes were interpreted by a neuromechanical network model consisting of five neuron groups in the brain respiratory center coupled with the mechanical properties of the respiratory system modeled as a simple Kelvin body. The model-based α for VT is 0.57, similar to the experimental data. While the α for TTOT was slightly lower than the experimental values, the model correctly predicted α for end-expiratory lung volumes (1.045). In conclusion, we propose that the correlations in the timing and amplitude of the physiological variables originate from the brain with the exception of end-expiratory lung volume, which shows the strongest correlations largely due to the contribution of the viscoelastic properties of the tissues. This cycle-by-cycle variability may have a significant impact on the functioning of adherent cells in the respiratory system.

Dosimetric effects within target and organs at risk of interfractional patient mispositioning in left breast cancer radiotherapy.

PURPOSE: To investigate the effects of interfraction setup uncertainties on the dose distribution within the clinical target volume (CTV) and the organs at risk (OAR) of left-sided breast cancer patients undergoing external radiotherapy. METHODS AND MATERIALS: Interfractional setup errors were assessed by measuring surface control points displacements during 89 irradiation sessions in 4 patients, by means of opto-electronic localization. The measured position deviations were fed back to the treatment planning system for the evaluation of the corresponding dosimetric effects within CTV and OARs (lung, heart). RESULTS: Results revealed errors above 5 mm on some of the control points, but corresponding volumetric variations were on average below 2% for both the CTV within the 95-105% dose range and the OARs receiving more than 50% and 90% of the prescribed dose. A specific sensitivity to the setup errors was found as a function of the treatment plan design, leading to isolated cases exhibiting volumetric variations of CTV and OARs exceeding 2%. CONCLUSIONS: This study confirms the potential increase of treatment quality provided by the systematic patient position verification and highlights the role of opto-electronic position detection systems for the real-time check of patient setup errors and the evaluation of the corresponding dosimetric consequences, as a way to achieve consistent dose delivery.

Effects of posture and bronchoconstriction on low-frequency input and transfer impedances in humans.

We simultaneously evaluated the mechanical response of the total respiratory system, lung, and chest wall to changes in posture and to bronchoconstriction. We synthesized the optimal ventilation waveform (OVW) approach, which simultaneously provides ventilation and multifrequency forcing, with optoelectronic plethysmography (OEP) to measure chest wall flow globally and locally. We applied an OVW containing six frequencies from 0.156 to 4.6 Hz to the mouth of six healthy men in the seated and supine positions, before and after methacholine challenge. We measured mouth, esophageal, and transpulmonary pressures, airway flow by pneumotachometry, and total chest wall, pulmonary rib cage, and abdominal volumes by OEP. We computed total respiratory, lung, and chest wall input impedances and the total and regional transfer impedances (Ztr). These data were appropriately sensitive to changes in posture, showing added resistance in supine vs. seated position. The Ztr were also highly sensitive to lung constriction, more so than input impedance, as the former is minimally distorted by shunting of flow into alveolar gas compression and airway walls. Local impedances show that, during bronchoconstriction and at typical breathing frequencies, the contribution of the abdomen becomes amplified relative to the rib cage. A similar redistribution occurs when passing from seated to supine. These data suggest that the OEP-OVW approach for measuring Ztr could noninvasively track important lung and respiratory conditions, even in subjects who cannot cooperate. Applications might range from routine evaluation of airway hyperreactivity in asthmatic subjects to critical conditions in the supine position during mechanical ventilation.

Determinants of exercise performance in normal men with externally imposed expiratory flow limitation.

To understand how externally applied expiratory flow limitation (EFL) leads to impaired exercise performance and dyspnea, we studied six healthy males during control incremental exercise to exhaustion (C) and with EFL at approximately 1. We measured volume at the mouth (Vm), esophageal, gastric and transdiaphragmatic (Pdi) pressures, maximal exercise power (W(max)) and the difference (Delta) in Borg scale ratings of breathlessness between C and EFL exercise. Optoelectronic plethysmography measured chest wall and lung volume (VL). From Campbell diagrams, we measured alveolar (PA) and expiratory muscle (Pmus) pressures, and from Pdi and abdominal motion, an index of diaphragmatic power (W(di)). Four subjects hyperinflated and two did not. EFL limited performance equally to 65% W(max) with Borg = 9-10 in both. At EFL W(max), inspiratory time (TI) was 0.66s +/- 0.08, expiratory time (TE) 2.12 +/- 0.26 s, Pmus approximately 40 cmH2O and DeltaVL-DeltaVm = 488.7 +/- 74.1 ml. From PA and VL, we calculated compressed gas volume (VC) = 163.0 +/- 4.6 ml. The difference, DeltaVL-DeltaVm-VC (estimated blood volume shift) was 326 ml +/- 66 or 7.2 ml/cmH2O PA. The high Pmus and long TE mimicked a Valsalva maneuver from which the short TI did not allow recovery. Multiple stepwise linear regression revealed that the difference between C and EFL Pmus accounted for 70.3% of the variance in DeltaBorg. DeltaW(di) added 12.5%. We conclude that high expiratory pressures cause severe dyspnea and the possibility of adverse circulatory events, both of which would impair exercise performance.

Respiratory muscle dynamics and control during exercise with externally imposed expiratory flow limitation.

To determine how decreasing velocity of shortening (U) of expiratory muscles affects breathing during exercise, six normal men performed incremental exercise with externally imposed expiratory flow limitation (EFLe) at approximately 1 l/s. We measured volumes of chest wall, lung- and diaphragm-apposed rib cage (Vrc,p and Vrc,a, respectively), and abdomen (Vab) by optoelectronic plethysmography; esophageal, gastric, and transdiaphragmatic pressures (Pdi); and end-tidal CO2 concentration. From these, we calculated velocity of shortening and power (W) of diaphragm, rib cage, and abdominal muscles (di, rcm, ab, respectively). EFLe forced a decrease in Uab, which increased Pab and which lasted well into inspiration. This imposed a load, overcome by preinspiratory diaphragm contraction. Udi and inspiratory Urcm increased, reducing their ability to generate pressure. Pdi, Prcm, and Wab increased, indicating an increased central drive to all muscle groups secondary to hypercapnia, which developed in all subjects. These results suggest a vicious cycle in which EFLe decreases Uab, increasing Pab and exacerbating the hypercapnia, which increases central drive increasing Pab even more, leading to further CO2 retention, and so forth.

The densitometric physical fractionator for counting neuronal populations: application to a mouse model of familial amyotrophic lateral sclerosis.

The method of the 'densitometric physical fractionator' presented here realizes an accurate and reproducible stereological quantification, not requiring a motorized or controlled z-axis, of cell populations. It includes a special software for the calibration of the optics alignment of the microscope and a semi-automatic procedure that integrates specific densitometric functions for image analysis, to identify the reference volume and the particle profiles. This improves the identification of the cells significantly, reduces variability in the subjective choice of the particles by the operators, and allows a consistent saving of time during the analysis. The method is proved to be unbiased and the accuracy and reproducibility of the results has been validated through intra- and inter-operator analyses. Furthermore, it has been applied to calculate the loss of spinal motor neurons during pathology progression in transgenic mice for superoxide-dismutase Cu/Zn dependent (SOD1) mutants, a model of amyotrophic lateral sclerosis (ALS).