Very low tidal volume ventilation with associated hypercapnia--effects on lung injury in a model for acute respiratory distress syndrome

Background

Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome.

Methodology/Principal Findings

In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8–10 ml/kg/PaCO₂ = 40 mm Hg; Group 2: tidal volume = 4–5 ml/kg/PaCO₂ = 80 mm Hg; Group 3: tidal volume = 3–4 ml/kg/PaCO₂ = 120 mm Hg; Group 4: tidal volume = 2–3 ml/kg/PaCO₂ = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO₂ were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4–5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy.

Conclusion

Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4–5 ml/kg/PaCO₂ 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained.     

Effect of respiratory muscle tension on lung volume.

The chest wall is modeled as a linear system for which the displacements of points on the chest wall are proportional to the forces that act on the chest wall, namely, airway opening pressure and active tension in the respiratory muscles. A standard theorem of mechanics, the Maxwell reciprocity theorem, is invoked to show that the effect of active muscle tension on lung volume, or airway pressure if the airway is closed, is proportional to the change of muscle length in the relaxation maneuver. This relation was tested experimentally. The shortening of the cranial-caudal distance between a rib pair and the sternum was measured during a relaxation maneuver. These data were used to predict the respiratory effect of forces applied to the ribs and sternum. To test this prediction, a cranial force was applied to the rib pair and a caudal force was applied to the sternum, simulating the forces applied by active tension in the parasternal intercostal muscles. The change in airway pressure, with lung volume held constant, was measured. The measured change in airway pressure agreed well with the prediction. In some dogs, nonlinear deviations from the linear prediction occurred at higher loads. The model and the theorem offer the promise that existing data on the configuration of the chest wall during the relaxation maneuver can be used to compute the mechanical advantage of the respiratory muscles.     

IL-13 is associated with reduced illness and replication in primary respiratory syncytial virus infection in the mouse

The role of IL-13 in respiratory syncytial virus (RSV) immunopathogenesis is incompletely described. To assess the effect of IL-13 on primary RSV infection, transgenic mice which either overexpress IL-13 in the lung (IL-13 OE) or non-transgenic littermates (IL-13 NT) were challenged intranasally with RSV. IL-13 OE mice had significantly decreased peak viral titers four days after infection compared to non-transgenic littermates. In addition, IL-13 OE mice had significantly lower RSV-induced weight loss and reduced lung IFN-gamma protein expression compared with IL-13 NT mice. In contrast, primary RSV challenge of IL-13 deficient mice resulted in a small, but statistically significant increase in viral titers on day four after infection, no difference in RSV-induced weight loss compared to wild type mice, and augmented IFN-gamma production on day 6 after infection. In STAT1-deficient (STAT1 KO) mice, where primary RSV challenge produced high levels of IL-13 production in the lungs, treatment with an IL-13 neutralizing protein resulted in greater peak viral titers both four and six days after RSV and greater RSV-induced weight loss compared to mice treated with a control protein. These results suggest that IL-13 modulates illness from RSV-infection.     

Hyperbaric hyperoxia exaggerates respiratory membrane defects in the copper-deficient rat lung

Scanning (SEM) and transmission electron microscopy (TEM) were used to examine the effect of dietary copper deficiency and hyperbaric hyperoxia, alone and in combination, on lung structure. Male, weanling Sprague-Dawley^† rats were fed a copper-deficient (CuD, 0.2 μg/g) or copper-adequate diet (CuA, 5.1 μg/g). After 35–41 d on their respective diets, rats from each group were placed inside a pressure vessel kept at 27°C under one of two pressure protcols. Air controls were maintained at 1 atm for 75 min. Rats exposed to oxygen were maintained at 1 atm of air plus 3 atm of oxygen for 1 h and then decompressed for 15 min. Under SEM, none of the treated lungs (CuD, CuA-O₂ exposed, or CuD-O₂ exposed) showed abnormal lung morphology from the conducting bronchioles down to the alveoli. Copper-deficient red blood cells were abnormally shaped. Under TEM, CuA-O₂-exposed lungs showed thicker respiratory membranes, especially basement membranes and endothelial cells, and alveolar Type II cells having more than the usual number of surfactant vacuoles. CuD lungs also showed thicker endothelial and basement membrane components of the respiratory membrane, but normal looking Type II cells. CuD-O₂-exposed lungs showed greatly thickened respiratory membranes and severe disruption of both endothelium and basement membrane and, judging by the increased number of nuclei per field, an increase in the number of both Type I and Type II cells. We conclude that copper deficiency enhances the damage caused by O₂ toxicity, an effect that may be caused by reduced antioxidant status.     

Effect of changes in lung volume on respiratory system compliance in newborn infants

Total respiratory system compliance (Crs) at volumes above the tidal volume (VT) was studied by use of the expiratory volume clamping (EVC) technique in 10 healthy sleeping unsedated newborn infants. Flow was measured with a pneumotachograph attached to a face mask and integrated to yield volume. Volume changes were confirmed by respiratory inductance plethysmography. Crs measured by EVC was compared with Crs during tidal breathing determined by the passive flow-volume (PFV) technique. Volume increases of approximately 75% VT were achieved with three to eight inspiratory efforts during expiratory occlusions. Crs above VT was consistently greater than during tidal breathing (P less than 0.0005). This increase in Crs likely reflects recruitment of lung units that are closed or atelectatic in the VT range. Within the VT range, Crs measured by PFV was compared with that obtained by the multiple-occlusion method (MO). PFV yielded greater values of Crs than MO (P less than 0.01). This may be due to braking of expiratory airflow after the release of an occlusion or nonlinearity of Crs. Thus both volume recruitment and airflow retardation may affect the measurement of Crs in unsedated newborn infants.     

Prenatal dexamethasone administration disrupts the pattern of cellular development in rat lung

To examine whether prenatal exposure to glucocorticoids could adversely affect subsequent cellular development of the lung, we administered 0.2 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19. Lungs of the offspring were then examined for patterns of cell acquisition (DNA) and growth (protein). DNA concentration (a marker of cell packing density) and DNA content (a measure of total cell numbers) were reduced during gestation, and the shortfalls in concentration persisted past weaning. Disruption of development was also apparent in the protein/DNA ratio, which was consistently elevated, a finding consistent with cellular hypertrophy. In addition, lung ODC became coupled to beta-adrenergic receptors prematurely in the dexamethasone group, suggesting that neural control of tissue differentiation is altered. These data indicate that prenatal glucocorticoids may compromise lung development through effects on cell replication and differentiation, which derive, in part, from alterations in the reception of trophic neural signals.     

Effect of lung volume on the respiratory action of the canine pectoral muscles.

Lung volume influences the mechanical action of the primary inspiratory and expiratory muscles by affecting their precontraction length, alignment with the rib cage, and mechanical coupling to agonistic and antagonistic muscles. We have previously shown that the canine pectoral muscles exert an expiratory action on the rib cage when the forelimbs are at the torso's side and an inspiratory action when the forelimbs are held elevated. To determine the effect of lung volume on intrathoracic pressure changes produced by the canine pectoral muscles, we performed isolated bilateral supramaximal electrical stimulation of the deep pectoral and superficial pectoralis (descending and transverse heads) muscles in 15 adult supine anesthetized dogs during hyperventilation-induced apnea. Lung volume was altered by application of a negative or positive pressure (+/- 30 cmH2O) to the airway. In all animals, selective electrical stimulation of the descending, transverse, and deep pectoral muscles with the forelimbs held elevated produced negative intrathoracic pressure changes (i.e., an inspiratory action). Moreover, with the forelimbs elevated, increasing lung volume decreased both pectoral muscle fiber precontraction length and the negative intrathoracic pressure changes generated by contraction of each of these muscles. Conversely, with the forelimbs along the torso, increasing lung volume lengthened pectoral muscle precontraction length and augmented the positive intrathoracic pressure changes produced by muscle contraction (i.e., an expiratory action). These results indicate that lung volume significantly affects the length of the canine pectoral muscles and their mechanical actions on the rib cage.     

Alterations in the pattern of arachidonate metabolism accompany rat macrophage differentiation in the lung

The present study was undertaken to investigate the changes in arachidonic acid (AA) metabolism which accompany rat macrophage (m phi) differentiation in the lung in order to determine whether these changes occur in the alveolar space or in the pulmonary interstitium, as well as the mechanisms responsible for such changes. Metabolism of endogenous and exogenous AA by cultured m phi obtained from the peritoneum (PM), the pulmonary interstitium (IM), and the alveolar spaces (AM) was examined by using HPLC and RIA. Although PM and AM released similar amounts of endogenous AA in response to both ionophore A23187 and the particulate zymosan, PM metabolized AA predominantly to cyclooxygenase (CO) products, whereas AM produced predominantly 5-lypoxygenase (5-LO) metabolites. IM synthesized a profile of eicosanoids which more closely resembled that of PM. Studies of the metabolism of exogenously supplied AA demonstrated that AM indeed had less CO activity than did PM. PM, but not AM, CO activity decreased during prolonged culture in air, suggesting the possibility that oxidative inactivation of CO plays a role in the decline in CO capacity which accompanies m phi differentiation in the lung. In contrast, the greater expression of 5-LO metabolism in AM than PM did not reflect mere differences in enzyme capacity, since upon activation of protein kinase C with PMA or oleoylacetylglycerol, ionophore-stimulated PM produced amounts of 5-LO products which were comparable to the amounts produced by AM stimulated with A23187 alone. These results indicate that increases in 5-LO metabolism and decreases in CO metabolism accompany rat m phi differentiation in the lung, that these changes occur largely in the alveolar space, and that the increased 5-LO capacity and decreased CO capacity are independently regulated by different mechanisms.     

Abnormality of an index of alveolar-capillary barrier permeability associated with respiratory tract infection in the rat

The study investigated the role of subclinical respiratory tract infection in producing an abnormality of lung function assessed by measuring an index of the permeability of the blood-gas barrier to 99mTcDTPA. Pasteurella pneumotropica was grown from throat swabs taken from 9 female rats age 10 weeks at the time of the experiment and housed under conventional husbandry conditions for 4 weeks previously. There was a significant association between the amount of bacteriological growth and an abnormality of the index of permeability. In contrast to this finding, there was no bacterial growth and no abnormality of function found in 12 female rats age 6 weeks, kept under strict barrier-maintained conditions. This finding emphasises the need for great care to be taken in the husbandry of animals used in scientific research.     

Effects of tidal volume and respiratory frequency on lung lymph flow.

Ventilation (V) increases lung lymph flow (Ql), but the separate effects of tidal volume (Vt) and frequency (f) and the role of V-induced changes in edema formation are poorly understood. An isolated, in situ sheep lung preparation was used to examine these effects. In eight sheep with f = 10 min(-1), results obtained during 30-min periods with Vt = 5 or 20 ml/kg were compared with values obtained during bracketed 30-min control periods (Vt = 12.5 ml/kg). Eight other sheep with constant Vt (12.5 ml/kg) were studied at f = 5 or 20 min(-1) and compared with f = 10 min(-1). Three additional groups of six sheep were perfused for 100 min with control V (10 ml/kg, 10 min(-1)). Vt was then kept constant or changed to 20 or 3 ml/kg during a second 100-min period. Increases in Vt or f increased Ql and vice versa, without corresponding effects on the rate of edema formation. For the same change in V, changing Vt had a greater effect on Ql than changing f. The change in Ql caused by an increase in Vt was significantly greater after the accumulation of interstitial edema. The change in Ql caused by a sustained increase in Vt was transient and did not correlate with the rate of edema formation, suggesting that V altered Ql through direct mechanical effects on edema-filled compartments and lymphatic vessels rather than through V-induced changes in fluid filtration.