Lung pathophysiology in patients with long COVID-19: one size definitely does not fit all.

Despite reduced resting lung volumes and D LCO, patients with long COVID and dyspnoea have similar physiological response to exercise to healthy subjects. D LCO impairment can marginally explain heterogeneity of complex syndromes such as long COVID. https://bit.ly/40j4aX6.

Plethysmographic assessment of tidal expiratory flow limitation.

Chronic obstructive pulmonary disease (COPD) patients often experience tidal expiratory flow-limitation (tEFL), a condition causing respiratory and cardiovascular detrimental effects. As the appearance of tEFL should increase expiratory (Rexp) relative to inspiratory (Rins) resistance, we hypothesized that Rexp/Rins can be used to detect tEFL. Rexp/Rins was measured with a commercial plethysmograph in 109 healthy subjects and, before and after bronchodilation (BD), in 64 COPD patients, 36 with and 28 without tEFL according to the NEP technique. Before BD, the median (interquartile range) of Rexp/Rins was significantly greater (P < 0.001) in COPD patients with tEFL (2.47(3.06;7.07)) than in COPD patients without tEFL (1.63(1.44;1.82)) and in healthy subjects (1.52(1.35;1.62)). In COPD patients Rexp/Rins above 1.98 predicted the presence of tEFL with 96 % specificity and 92 % sensitivity, Rexp2/Rins performing even better. After BD the predictive ability of Rexp/Rins slightly declined, but remained elevated. The non-invasive measurement of Rexp/Rins is an easy, inexpensive, routinely usable method to detect tEFL in spontaneously breathing COPD subjects.

Diagnostic Insights from Plethysmographic Alveolar Pressure Assessed during Spontaneous Breathing in COPD Patients.

Since its introduction in the clinical practice, body plethysmography has assisted pneumologists in the diagnosis of respiratory diseases and patients' follow-up, by providing easy assessment of absolute lung volumes and airway resistance. In the last decade, emerging evidence suggested that estimation of alveolar pressure by electronically-compensated plethysmographs may contain information concerning the mechanics of the respiratory system which goes beyond those provided by the simple value of airway resistance or conductance. Indeed, the systematic study of expiratory alveolar pressure-flow loops produced during spontaneous breathing at rest has shown that the marked expansion of expiratory loops in chronic obstructive pulmonary disease patients mainly reflects the presence of tidal expiratory flow-limitation. The presence of this phenomenon can be accurately predicted on the basis of loop-derived parameters. Finally, we present results suggesting that plethysmographic alveolar pressure may be used to estimate non-invasively intrinsic positive end-expiratory pressure (PEEPi) in spontaneously breathing patients, a task which previously could be only accomplished by introducing a balloon-tipped catheter in the esophagus.

Heliox administration in anesthetized rabbits with spontaneous inspiratory flow limitation.

We investigated the effects of heliox administration (80% helium in O2) on tidal inspiratory flow limitation (tIFL) occurring in supine anesthetized spontaneously breathing rabbits, regarded as an animal model of obstructive apnea-hypopnea syndrome. 22 rabbits were instrumented to record oro-nasal mask flow, airway opening, tracheal and esophageal pressures, and diaphragm and genioglossus electromyographic activities while breathing either room air or heliox, and, in 12 rabbits, also during the application of continuous positive airway pressure (CPAP; 6 cmH2O). For the group, heliox increased peak inspiratory flow, ventilation (18 ± 11%), peak inspiratory tracheal and dynamic transpulmonary pressures, but in no animal eliminated tIFL, as instead CPAP did in all. Muscle activities were unaffected by heliox. In the presence of IFL the increase in flow with heliox (ΔV̇ifl) varied markedly among rabbits (2 to 49%), allowing the distinction between responders and non-responders. None of the baseline variables discriminated responders and non-responders. However, fitting the Rohrer equation (R = K1 + K2V̇) to the tracheal pressure-flow relationship over the first 0.1 s of inspiration while breathing air allowed such discrimination on the basis of larger K2 in responders (0.005 ± 0.002 versus 0.002 ± 0.001 cmH2O·s2·ml-2; P < 0.001), suggesting a corresponding difference in the relative contribution of laminar and turbulent flow. The differences in ΔV̇ifl between responders and non-responders were simulated by modeling the collapsible segment of the upper airways as a non-linear resistor and varying its pressure-volume curve, length, and diameter, thus showing the importance of mechanical and geometrical factors in determining the response to heliox in the presence of tIFL.NEW & NOTEWORTHY In an obstructive sleep apnea rabbit model, heliox never abolishes tidal inspiratory flow limitation (IFL), but increases inspiratory flow and tidal volume, substantially in some and nearly nil in other animals. Positive response to heliox cannot be predicted on the basis of breathing pattern characteristics or upper airway resistance that preceded IFL onset, but is related to the mechanical and geometrical features of upper airway collapsible segment, as indicated by model simulation.

Tidal expiratory flow limitation induces expiratory looping of the alveolar pressure-flow relation in COPD patients.

During spontaneous breathing at rest, the alveolar pressure (Palv)-flow (V̇) relation exhibits a prominent expiratory loop in many chronic obstructive pulmonary disease (COPD) patients. Among the possible determinants of the loop, tidal expiratory flow limitation (tEFL) may be the main responsible. To compare the characteristics of the expiratory loop in COPD patients with flow limitation (FL) and without flow limitation (NFL), tEFL was assessed with the negative expiratory pressure technique in stable mild to very severe COPD patients undergoing body plethysmography before and after bronchodilation (BD), an intervention that is able to reduce mechanical heterogeneity, recruitment/derecruitment, and gas trapping but rarely abolishes tEFL. The magnitude of the expiratory loop was indexed by the integral of Palv on V̇ during expiration (Aexp). Before BD, Aexp was 360% greater in FL (n = 35) than in NFL (n = 25) patients (P < 0.001). After BD, Aexp was unchanged in NFL patients (ΔAexp 0%, P = 0.882) and slightly decreased in FL patients who remained FL (n = 32, ΔAexp -17%, P = 0.064). Three FL patients became NFL after BD, and their Aexp decreased markedly (ΔAexp -61%), reaching values similar to those observed in NFL patients at baseline. In conclusion, the greater Aexp measured in FL relative to NFL COPD patients, its relative invariance after BD when flow limitation persists, and its fall when flow limitation is abolished indicate that tEFL is a major determinant of the magnitude of the expiratory loop. Furthermore, Aexp can be used as a predictor of the presence of tEFL.NEW & NOTEWORTHY In stable chronic obstructive pulmonary disease (COPD) patients spontaneously breathing at rest, tidal expiratory flow limitation is the major determinant of the occurrence of expiratory looping in the plethysmographic flow-alveolar pressure diagram. In these patients the magnitude and the characteristics of the loop can be used as predictors of the presence of tidal expiratory flow limitation.

The development of various forms of lung injury with increasing tidal volume in normal rats.

Sixty-three, open-chest normal rats were subjected to mechanical ventilation (MV) with tidal volumes (VT) ranging from 7.5-39.5ml kg-1 and PEEP 2.3 cmH2O. Arterial blood gasses and pressure, and lung mechanics were measured during baseline ventilation (VT = 7.5ml kg-1) before and after test ventilation, when cytokine, von Willebrand factor (vWF), and albumin concentration in serum and broncho-alveolar lavage fluid (BALF), wet-to-dry weight ratio (W/D), and histologic injury scores were assessed. Elevation of W/D and serum vWF and cytokine concentration occurred with VT > 25ml kg-1. With VT > 30ml kg-1 cytokine and albumin concentration increased also in BALF, arterial oxygen tension decreased, lung mechanics and histology deteriorated, while W/D and vWF and cytokine concentration increased further. Hence, the initial manifestation of injurious MV consists of damage of extra-alveolar vessels leading to interstitial edema, as shown by elevated vWF and cytokine levels in serum but not in BALF. Failure of the endothelial-epithelial barrier occurs at higher stress-strain levels, with alveolar edema, small airway injury, and mechanical alterations.

Standard and viscoelastic mechanical properties of respiratory system compartments in dogs: Effect of volume, posture, and shape.

In 9 anesthetized, paralyzed dogs lung and chest-wall standard (viscous resistance, Rint, and quasi-static elastance, Est) and viscoelastic parameters (resistance, Rvel, and time constant, τvel) were measured in the supine posture before and after rib-cage block, after application of an expiratory threshold load, and after 75° head-up tilting before and after wide chest opening. Lung and chest-wall τvel were the same under all conditions. Rvel was independent of volume and posture, and greater for the lung. Chest-wall Rint was independent of flow, volume, and posture. Lung Rint decreased with increasing volume. Chest-wall Rint, Est and Rvel increased with rib-cage block, allowing the assessment of both abdominal-wall and rib-cage characteristics. When chest opening did not elicit bronchoconstriction, the decrease of Rvel was ∼6%. Main conclusions: lung and chest-wall exhibit linear tissue viscoelasticity within the range studied; rib-cage and abdomen characteristics are similar, and asynchronous motion is not expected at physiological respiratory rates; in normal lungs, heterogeneity of parallel time constants plays a marginal role.

Plethysmographic Loops: A Window on the Lung Pathophysiology of COPD Patients.

Plethysmographic alveolar pressure-flow (Palv-F) loops contain potentially relevant information about the pathophysiology of chronic obstructive pulmonary disease (COPD), but no quantitative analysis of these loops during spontaneous breathing has ever been performed. The area of the loop's inspiratory (Ains) and expiratory portion (Aexp), and the difference between the end-expiratory and end-inspiratory alveolar pressure (ΔPalv) were measured in 20 young, 20 elderly healthy subjects, and 130 stable COPD patients. Ains and ΔPalv increased by 55 and 78% from young to elderly subjects, and by 107 and 122% from elderly subjects to COPD patients, reflecting changes in mechanical heterogeneity, lung-units recruitment/derecruitment, and possibly air trapping occurring with aging and/or obstructive disease. Aexp increased by 38% from young to elderly subjects, and by 198% from elderly subjects to COPD patients, consistent with the additional contribution of tidal expiratory flow-limitation, which occurs only in COPD patients and affects Aexp only. In COPD patients, Aexp and ΔPalv showed a significant negative correlation with VC, FEV1, IC, and a significant positive correlation with RV/TLC. The results suggest that the analysis of plethysmographic Palv-F loops provides an insight of the pathophysiological factors, especially tidal expiratory flow-limitation, that affect lung function in COPD patients.

Airway occlusion assessed by single breath N2 test and lung P-V curve in healthy subjects and COPD patients.

PURPOSE: To determine whether the analysis of the slow expiratory transpulmonary pressure-volume (PL-V) curve provides an alternative to the single-breath nitrogen test (SBN) for the assessment of the closing volume (CV). METHODS: SBN test and slow deflation PL-V curve were simultaneously recorded in 40 healthy subjects and 43 COPD patients. Onset of phase IV identified CV in SBN test (CVSBN), whereas in the PL-V curve CV was identified by: a) deviation from the exponential fit (CVexp), and b) inflection point of the interpolating sigmoid function (CVsig). RESULTS: In the absence of phase IV, COPD patients exhibited a clearly discernible inflection in the PL-V curve. In the presence of phase IV, CVSBN and CVexp coincided (CVSBN/CVexp=1.04±0.04 SD), whereas CVsig was systematically larger (CVsig/CVexp=2.1±0.86). CONCLUSION: The coincidence between CVSBN and CVexp, and the presence of the inflection in the absence of phase IV indicate that the deviation of the PL-V curve from the exponential fit reliably assesses CV.

Friction and morphology of pleural mesothelia.

To verify the hypothesis that by enmeshing lubricants, microvilli reduce the coefficient of kinetic friction (µ) of pleural mesothelium, µ was measured during reciprocating sliding of rabbit's visceral against parietal pleura before and after addition of hyaluronan, and related to the morphological features of the microvillar network. Because no relation was found between µ or µ changes after hyaluronan and microvillar characteristics, the latter are not determinants of the frictional forces which oppose sliding of normal mesothelial surfaces under physiological conditions, nor of the effects of hyaluronan. Addition of hyaluronan increased µ slightly but significantly in normal specimens, probably by altering the physiological mix of lubricants, but decreased µ of damaged mesothelia, suggesting protective, anti-abrasion properties. Indeed, while sliding of an injured against a normal pleura heavily damaged the latter and increased µ when Ringer was interposed between the surfaces, both effects were limited or prevented when hyaluronan was interposed between the injured and normal pleura before onset of sliding.

Assessment of acute bronchodilator effects from specific airway resistance changes in stable COPD patients.

BACKGROUND: In COPD patients, reversibility is currently evaluated from the changes of forced expiratory volume at 1s (ΔFEV1) and forced vital capacity (ΔFVC). By lowering peripheral airway smooth muscle tone, bronchodilators should decrease dynamic hyperinflation, gas trapping, and possibly dyspnea at rest. Hence, we hypothesize that specific airway resistance changes (ΔsRAW) should better characterize the acute response to bronchodilators. METHODS: On two days, 60 COPD patients underwent dyspnea evaluation (VAS score) and pulmonary function testing at baseline and one hour after placebo or 300µg indacaterol administration. RESULTS: Spirographic and ΔsRAW-based criteria identified as responders 24 and 45 patients, respectively. ΔsRAW correlated with changes of intrathoracic gas volume (ΔITGV) (r=0.61; p<0.001), residual volume (ΔRV) (r=0.60; p<0.001), ΔFVC (r=0.44; p=0.001), and ΔVAS (r=0.73; p<0.001), while ΔFEV1 correlated only with ΔFVC (r=0.34; p=0.008). Significant differences in terms of ΔITGV (p=0.002), ΔRV (p=0.023), and ΔVAS (p<0.001) occurred only if patients were stratified according to ΔsRAW. CONCLUSIONS: In assessing the acute functional effect of bronchodilators, ΔsRAW-based criterion is preferable to FEV1-FVC-based criteria, being more closely related to bronchodilator-induced improvements of lung mechanics and dyspnea at rest.

Effects of various modes of mechanical ventilation in normal rats.

BACKGROUND: Recent studies in healthy mice and rats have reported that positive pressure ventilation delivered with physiological tidal volumes at normal end-expiratory volume worsens lung mechanics and induces cytokine release, thus suggesting that detrimental effects are due to positive pressure ventilation per se. The aim of this study in healthy animals is to assess whether these adverse outcomes depend on the mode of mechanical ventilation. METHODS: Rats were subjected to 4 h of spontaneous, positive pressure, and whole-body or thorax-only negative pressure ventilation (N = 8 per group). In all instances the ventilatory pattern was that of spontaneous breathing. Lung mechanics, cytokines concentration in serum and broncho-alveolar lavage fluid, lung wet-to-dry ratio, and histology were assessed. Values from eight animals euthanized shortly after anesthesia served as control. RESULTS: No evidence of mechanical ventilation-dependent lung injury was found in terms of lung mechanics, histology, or wet-to-dry ratio. Relative to control, cytokine levels and recruitment of polymorphonuclear leucocytes increased slightly, and to the same extent with spontaneous, positive pressure, and whole-body negative pressure ventilation. Thorax-only negative pressure ventilation caused marked chest and lung distortion, reversible increase of lung elastance, and higher polymorphonuclear leucocyte count and cytokine levels. CONCLUSION: Both positive and negative pressure ventilation performed with tidal volumes and timing of spontaneous, quiet breathing neither elicit an inflammatory response nor cause morpho-functional alterations in normal animals, thus supporting the notion of the presence of a critical volume threshold above which acute lung injury ensues. Distortion of lung parenchyma can induce an inflammatory response, even in the absence of volotrauma.

Esophageal pressure as an estimate of average pleural pressure with lung or chest distortion in rats.

Pressure-volume curves of the lungs and chest wall require knowledge of an effective 'average' pleural pressure (Pplav), and are usually estimated using esophageal pressure as Ples-V and Pwes-V curves. Such estimates could be misleading when Ppl becomes spatially non-uniform with lung lavage or shape distortion of the chest. We therefore measured Ples-V and Pwes-V curves in conditions causing spatial non-uniformity of Ppl in rats. Ples-V curves of normal lungs were unchanged by chest removal. Lung lavage depressed PLes-V but not Pwes-V curves to lower volumes, and chest removal after lavage increased volumes at PL≥15cmH2O by relieving distortion of the mechanically heterogeneous lungs. Chest wall distortion by ribcage compression or abdominal distension depressed Pwes-V curves and Ples-V curves of normal lungs only at Pl≥3cmH2O. In conclusion, Pes reflects Pplav with normal and mechanically heterogeneous lungs. With chest wall distortion and dependent deformation of the normal lung, changes of Ples-V curves are qualitatively consistent with greater work of inflation.

Plasma membrane disruptions with different modes of injurious mechanical ventilation in normal rat lungs*.

OBJECTIVES: Plasma membrane disruptions are caused by excessive mechanical stress and thought to be involved in inflammatory mediator upregulation. Presently, plasma membrane disruption formation has been studied only during mechanical ventilation with large tidal volumes and limitedly to subpleural alveoli. No information is available concerning the distribution of plasma membrane disruptions within the lung or the development of plasma membrane disruptions during another modality of injurious mechanical ventilation, i.e., mechanical ventilation with eupneic tidal volume (7 mL · kg) at low end-expiratory lung volume. The aim of this study is to assess whether 1) mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume causes plasma membrane disruptions; and 2) the distribution of plasma membrane disruptions differs from that of mechanical ventilation with large tidal volume at normal end-expiratory lung volume. DESIGN: Experimental animal model. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Plasma membrane disruptions have been detected as red spots in gelatin-included slices of rat lungs stained with ethidium homodimer-1 shortly after anesthesia (control) after prolonged mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume followed or not by the restoration of physiological end-expiratory lung volume and after prolonged mechanical ventilation with large tidal volumes and normal end-expiratory lung volume. MEASUREMENTS AND MAIN RESULTS: Plasma membrane disruptions increased during mechanical ventilation at low end-expiratory lung volume, mainly at the bronchiolar level. Resealing of most plasma membrane disruptions occurred on restoration of normal end-expiratory lung volume. Mechanical ventilation with large tidal volume caused the appearance of plasma membrane disruptions, both bronchiolar and parenchymal, the latter to a much greater extent than with mechanical ventilation at low end-expiratory lung volume. The increase of plasma membrane disruptions correlated with the concomitant increase of airway resistance with both modes of mechanical ventilation. CONCLUSIONS: : Amount and distribution of plasma membrane disruptions between small airways and lung parenchyma depends on the type of injurious mechanical ventilation. This could be relevant to the release of inflammatory mediators.

Maintaining end-expiratory transpulmonary pressure prevents worsening of ventilator-induced lung injury caused by chest wall constriction in surfactant-depleted rats.

OBJECTIVE: To see whether in acute lung injury 1) compression of the lungs caused by thoracoabdominal constriction degrades lung function and worsens ventilator-induced lung injury; and 2) maintaining end-expiratory transpulmonary pressure by increasing positive end-expiratory pressure reduces the deleterious effects of chest wall constriction. DESIGN: Experimental study in rats. SETTING: Physiology laboratory. INTERVENTIONS: Acute lung injury was induced in three groups of nine rats by saline lavage. Nine animals immediately killed served as a control group. Group L had lavage only, group LC had the chest wall constricted with an elastic binder, and group LCP had the same chest constriction but with positive end-expiratory pressure raised to maintain end-expiratory transpulmonary pressure. After lavage, all groups were ventilated with the same pattern for 1½ hrs. MEASUREMENTS AND MAIN RESULTS: Transpulmonary pressure, measured with an esophageal balloon catheter, lung volume changes, arterial blood gasses, and pH were assessed during mechanical ventilation. Lung wet-to-dry ratio, albumin, tumor necrosis factor-α, interleukin-1ß, interleukin-6, interleukin-10, and macrophage inflammatory protein-2 in serum and bronchoalveolar lavage fluid and serum E-selectin and von Willebrand Factor were measured at the end of mechanical ventilation. Lavage caused hypoxemia and acidemia, increased lung resistance and elastance, and decreased end-expiratory lung volume. With prolonged mechanical ventilation, lung mechanics, hypoxemia, and wet-to-dry ratio were significantly worse in group LC. Proinflammatory cytokines except E-selectin were elevated in serum and bronchoalveolar lavage fluid in all groups with significantly greater levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in group LC, which also exhibited significantly worse bronchiolar injury and greater heterogeneity of airspace expansion at a fixed transpulmonary pressure than other groups. CONCLUSIONS: Chest wall constriction in acute lung injury reduces lung volume, worsens hypoxemia, and increases pulmonary edema, mechanical abnormalities, proinflammatory mediator release, and histologic signs of ventilator-induced lung injury. Maintaining end-expiratory transpulmonary pressure at preconstriction levels by adding positive end-expiratory pressure prevents these deleterious effects.

Motor control of the diaphragm in anesthetized rabbits.

Diaphragmatic regions are recruited in a specialized manner either as part of a central motor program during non-respiratory maneuvers, e.g. vomiting, or because of reflex responses, e.g. esophageal distension. Some studies in cats and dogs suggest that crural and costal diaphragm may be differentially activated also in response to respiratory stimuli from chemoreceptors or lung and chest wall mechanoreceptors. To verify whether this could occur also in other species, the EMG activity from the sternal, costoventral, costodorsal, and crural diaphragm was recorded in 42 anesthetized rabbits in response to various respiratory maneuvers, such as chemical stimulation, mechanical loading, lung volume and postural changes before and after vagotomy, or a non-respiratory maneuver such as esophageal distension. Regional activity was evaluated from timing of the raw EMG signal, and amplitude and shape of the moving average EMG. In all animals esophageal distension caused greater inhibition of the crural than sternal and costal diaphragm, whereas under all the other conditions differential diaphragmatic activation never occurred. These results indicate that in response to respiratory stimuli the rabbit diaphragm behaves as a single unit under the command of the central respiratory control system.

Expiratory flow-limitation and heliox breathing in resting and exercising COPD patients.

In 26 stable patients with chronic obstructive pulmonary disease, tidal expiratory flow-limitation (TEFL), inspiratory capacity, breathing pattern and dyspnea sensation were assessed during air and heliox (20% O(2) in He) breathing at rest and during exercise up to 2/3 maximal work rate. Breathing air, the 13 patients with TEFL at rest remained flow-limited also during exercise, while 7 of the non-flow-limited patients became flow-limited; tidal volume increased more in non-flow-limited patients, whereas inspiratory capacity decreased in flow-limited and increased in the non-flow-limited patients. Heliox did not abolish flow-limitation, had no effect on breathing pattern, reduced exercise dynamic hyperinflation in 25% of the flow-limited patients, depending on the degree of the dynamic hyperinflation on air, and lessened dyspnea sensation in all patients. Hence, the presence of TEFL has no systematic effects on the respiratory response to heliox, and the heliox-induced decrease of exercise dyspnea is not mainly due to changes in dynamic hyperinflation or TEFL.

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats.

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production.

The fall in exhaled nitric oxide with ventilation at low lung volumes in rabbits: an index of small airway injury.

The mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration occurring in normal, anesthetized open chest rabbits with prolonged mechanical ventilation (MV) at low lung volume have been investigated. NOe, pH of exhaled vapor condensate, serum prostaglandin E(2), and F(2alpha), tumor necrosis factor (TNF-alpha), PaO(2), PaCO(2), pHa, and lung mechanics were assessed before, during, and after 3-4h of MV at zero end-expiratory pressure (ZEEP), with fixed tidal volume (9 ml kg(-1)) and frequency, as well as before and after 3-4h of MV on PEEP only. Lung histology and wet-to-dry ratio (W/D), and prostaglandin and TNF-alpha in bronchoalveolar lavage fluid (BALF) were also assessed. While MV on PEEP had no effect on the parameters above, MV on ZEEP caused a marked fall (45%) of NOe, with a persistent increase of airway resistance (45%) and lung elastance (12%). Changes in NOe were independent of prostaglandin and TNF-alpha levels, systemic hypoxia, hypercapnia and acidosis, bronchiolar and alveolar interstitial edema, and pH of exhaled vapor condensate. In contrast, there was a significant relationship between the decrease in NOe and bronchiolar epithelial injury score. This indicates that the fall in NOe, which occurs in the absence of an inflammatory response, is due to the epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small airways with MV on ZEEP, and suggests its use as a sign of peripheral airway injury.