Effect of pentoxifylline on hemodynamics, alveolar fluid reabsorption, and pulmonary edema in a model of acute lung injury

We investigated the effect of pentoxifylline (PTX) on the development of pulmonary edema in a model of adult respiratory distress syndrome in rabbits. Lung injury was induced by repeated saline lavages in adult rabbits weighing 2.5 to 3.5 kg. Rabbits pretreated with PTX (20 mg/kg bolus followed by 20 mg/kg/h infusion) developed significantly lower amounts of lung edema 4 h after saline lavage (extravascular lung water to dry weight ratio [W/D], 6.9 +/- 0.6 SD versus 8.9 +/- 0.5 in control animals). PTX produced a 25% increase in cardiac output, but there were no differences between treated and untreated groups in calculated pulmonary vascular resistance or microvascular pressure. To determine whether PTX could have lowered pulmonary venous resistance and thus lowered effective microvascular pressure for fluid filtration, we directly measured pulmonary artery and left atrial pressures, and measured by micropuncture the pressure in 20 to 40 microns subpleural venules in four open-chested rabbits 3 to 4 h after lavage. Venous resistance was low (venous pressure drop 0.9 +/- 0.1 mm Hg) and was unchanged by PTX infusion. To determine if PTX decreased lung water by accelerating active alveolar fluid reabsorption, a single 60-ml aliquot of saline was instilled into the lungs of normal rabbits treated with saline or PTX. Both groups had a similar decrease in lung water content 1 and 4 h later. Our data indicate that PTX reduces edema formation in rabbits after saline lavage, not by lowering microvascular pressures for fluid filtration or by acceleration alveolar fluid reabsorption, but possibly by its anti-inflammatory effect on neutrophil function.     

Effect of corticosteroid on lung parenchyma remodeling at an early phase of acute lung injury

In vivo (lung resistive and viscoelastic pressures and static elastance) and in vitro (tissue resistance, elastance, and hysteresivity) respiratory mechanics were analyzed 1 and 30 days after saline (control) or paraquat (P [10 and 25 mg/kg intraperitoneally]) injection in rats. Additionally, P10 and P25 were treated with methylprednisolone (2 mg/kg intravenously) at 1 or 6 hours after acute lung injury (ALI) induction. Collagen and elastic fibers were quantified. Lung resistive and viscoelastic pressures and static elastance were higher in P10 and P25 than in the control. Tissue elastance and resistance augmented from control to P10 (1 and 30 days) and P25. Hysteresivity increased in only P25. Methylprednisolone at 1 or 6 hours attenuated in vivo and in vitro mechanical changes in P25, whereas P10 parameters were similar to the control. Collagen increment was dose and time dependent. Elastic fibers increased in P25 and at 30 days in P10. Corticosteroid prevented collagen increment and avoided elastogenesis. In conclusion, methylprednisolone led to a complete maintenance of in vivo and in vitro respiratory mechanics in mild lesion, whereas it minimized the changes in tissue impedance and extracellular matrix in severe ALI. The beneficial effects of the early use of steroids in ALI remained unaltered at Day 30.     

Suture or prosthetic reconstruction of experimental diaphragmatic defects

OBJECTIVE: Diaphragmatic reconstruction may cause several respiratory changes. The aims of the present study were to evaluate the respiratory changes induced by two methods of diaphragmatic reconstruction. METHODS: Two groups of rats with an experimental diaphragmatic defect were studied. In one group (n = 5), diaphragmatic resection was followed by stitching together the borders of the wound (SUT); in another group (n = 5), the defect was repaired by suturing in a polytetrafluoroethylene (PTFE) patch. All animals were sedated, anesthetized, paralyzed, and mechanically ventilated. Spirometry, respiratory mechanics, and thoracoabdominal morphometry were evaluated before and after diaphragmatic reconstruction. RESULTS: The suture of the diaphragm significantly decreased FVC and FEV(1), and increased respiratory system, lung, and chest wall static and dynamic elastances and viscoelastic/inhomogeneous pressures in relation to their respective control values. On the other hand, diaphragmatic reconstruction with PTFE increased only respiratory system, lung, and chest wall static elastances. In addition, respiratory system, pulmonary, and chest wall viscoelastic/inhomogeneous pressures and dynamic elastances, as well as respiratory system and lung elastances, were significantly greater in SUT than in PTFE. Lateral diameter at the level of the xiphoid and cephalocaudal pulmonary diameter diminished only in the SUT group. CONCLUSIONS: The reconstruction of the diaphragm with PTFE might be preferred to simple suture for surgical repair of large diaphragmatic defects, at least from a mechanical standpoint.     

Pulmonary morphofunctional effects of acute myocardial infarction.

Acute myocardial infarction (AMI) may yield several respiratory changes. Nevertheless, no comprehensive pulmonary morphological/physiological correlation has been performed under this condition. The aims of the present investigation were: 1) to determine the respiratory parameters in an experimental model of coronary artery occlusion, 2) to relate these results to findings from lung histopathology, and 3) to evaluate the effects of propranolol used prior to AMI. Twenty-eight rats were anaesthetized and mechanically ventilated. In the control group (C), a suture line was passed around the left anterior descending coronary artery (LADCA). The infarct group (I) was similarly prepared but the LADCA was ligated and infarct resulted. In the control/propranolol (CP) and infarct/propranolol (IP) groups, propranolol was intravenously injected 5 min before surgery as performed in groups C and I, respectively. Lung static (EL,st) and dynamic (EL,dyn) elastances, airway resistance (RL,int), and viscoelastic/inhomogeneous pressure (deltaP2L) were determined before and 30, 60 and 120 min after surgery. In group I, EL,st, EL,dyn, RL,int and deltaP2L increased progressively throughout the experiment, and were higher than those found in groups C, CP and IP. All respiratory parameters but EL,st remained unaltered in group IP. Lung histopathological examination demonstrated alveolar, interstitial and intrabronchial oedema in group I. Group IP showed only interstitial oedema. Acute myocardial infarction yields lung resistive, elastic and viscoelastic changes. The last two results from alveolar and interstitial oedema, respectively. The previous use of propranolol diminishes respiratory changes.     

The Effect of Experimental Pleurodesis Caused by Aluminum Hydroxide on Lung and Chest Wall Mechanics

The aim of this study was to evaluate the effect of a chemical sclerosing agent, aluminum hydroxide, on pleural remodeling and on respiratory mechanics in rats. Saline (2 mL) or aluminum hydroxide [2 mL (0.15 g/mL)] was instilled intrapleurally in anesthetized male rats. The animals were studied 7 or 30 days after the instillation. Respiratory system, lung, and chest wall elastic, resistive, and viscoelastic/inhomogeneous pressures were measured by the end-inflation occlusion method. We studied the pleural remodeling process by means of semiquantitative analysis of the induced inflammation and quantitative analysis of the collagen extracellular matrix component. The effects on the underlying lung were analyzed morphometrically. Chest wall elastic and viscoelastic pressures increased after aluminum hydroxide instillation independent of time after instillation. Pleural inflammation was observed 7 days after instillation, while pleural adherence with a marked increase in the type I/type III collagen ratio was present 30 days after instillation. Histological examination demonstrated no differences in lung parenchyma among the groups. In conclusion, the present model describes the establishment of pleurodesis by aluminum hydroxide, which thwarts the normal chest wall mechanical profile without inducing any changes in the underlying lungs. The results were disclosed by both mechanical and morphological evaluation of the pleural remodeling.     

Reexpansion pulmonary edema.

A case of pulmonary edema following reexpansion of a collapsed lung due to pneumothorax is described and illustrated. The importance of recognizing this relatively uncommon phenomenon is stressed. The development of such edema can be prevented by avoiding application of sudden and excessive negative pleural pressures during the evacuation of a pneumothorax or a pleural effusion. The edema generally occurs in a lung that has been collapsed for more than three days. The importance of the duration of pulmonary collapse in the causation of edema is demonstrated in this patient.     

Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury.

The effects of LASSBio596, a phosphodiesterase type-4 and -5 inhibitor, were tested in Escherichia coli lipopolysaccharide (LPS)-induced acute lung injury. Twenty-four BALB/c mice were randomly divided into four groups. In the control group, saline (0.05 mL) was injected intratracheally (i.t.). The LPS group received LPS (10 microg i.t., 0.05 mL). In the LASSBio596 groups, LASSBio596 (10 mg x kg(-1), 0.2 mL) was injected intraperitoneally 1 h before or 6 h after LPS administration. After 24 h, in vivo (lung resistive and viscoelastic pressures, and static and dynamic elastances) and in vitro (tissue resistance, elastance and hysteresivity) pulmonary mechanics, lung morphometry and collagenous fibre content were computed. Neutrophils and tumour necrosis factor (TNF)-alpha levels were evaluated in the bronchoalveolar lavage fluid. LASSBio596 prevented the changes in lung mechanics, and inhibited neutrophilic recruitment, TNF-alpha release, bronchoconstriction, alveolar collapse and the increment of collagen fibre content induced by LPS, independently of the moment of injection. In conclusion, LASSBio596 modulated the lung inflammatory process and had the potential to block fibroproliferation. Thus, agents that inhibit phosphodiesterase 4 and 5 simultaneously may be a useful adjunct therapy for acute lung injury.     

Non-linear evaluation of respiratory mechanics during laparoscopic cholecystectomy

BACKGROUND/AIMS: Laparoscopic cholecystectomy is accompanied by significant increase of the respiratory system elastic and resistive properties. These changes are completely abolished after peritoneal deflation. In the present study we examine the volume and flow dependence of respiratory mechanics during four operation phases. METHODOLOGY: Airway pressure and flow were recorded from 17 patients undergoing laparoscopic cholecystectomy. Measurements were done at 4 distinct phases: 1) Before the induction of pneumoperitoneum. 2) Five minutes after pneumoperitoneum induction at Trendelenburg position. 3) Five minutes after positioning the patient at reverse. Trendelenburg. 4) Five minutes after the peritoneal deflation. Data of airway pressure, flow and volume were treated according to the non-linear regression model: Paw = E1.V + E2.V2 + k1.V' + k2.V'. |V'| + k3.V.V' + EEP. RESULTS: The induction of pneumoperitoneum results in: Significant increase of linear elastance and resistance and significant decrease of flow and volume dependence of resistance. No significant changes are noted in volume dependence of elastance and end-expiratory pressure. CONCLUSIONS: The pneumoperitoneum and not the body position causes the changes in respiratory mechanics and their dependencies during laparoscopic cholecystectomy, which, although important, do not predispose to major risks (lung overdistension, alveolar collapse) and they are reversed after peritoneal deflation.     

Scorpion venom decreases lung liquid clearance in rats

It has been reported that scorpion venom causes respiratory failure and pulmonary edema. However, the effects of this toxin on lung edema clearance have not been previously studied. We examined the effects of scorpion (Tityus serrulatus) venom on the ability of the lung to clear fluid and on alveolar epithelial Na,K-ATPase. The wet-to-dry lung weight ratio was increased in anesthetized rats injected intraperitonally with scorpion venom. Lung edema clearance decreased by up to approximately 60% in rats injected with the venom. Na,K-ATPase alpha1- and beta1-subunit protein abundance and activity decreased at the basolateral membranes of alveolar epithelial type II cells incubated with scorpion venom as compared with that of control animals. There was no difference in cell injury in alveolar epithelial type II cells incubated with scorpion venom for 60 minutes compared with that of control animals. We provide here the first evidence that scorpion venom decreases lung liquid clearance, probably by downregulating Na,K-ATPase in the alveolar epithelium.     

Interstitial pulmonary edema

Florid pulmonary edema is frequently preceded by interstitial edema formation. Because of alterations in the balance of oncotic and hydrostatic pressures between the capillary and lung interstitium or changes in capillary permeability, edema fluid forms in the interstitial spaces of the lung. Once the capacitance of the pulmonary lymphatics is exceeded, interstitial and alveolar edemas become more prominent. Bronchoconstriction and increased vascular resistance lead to ventilation-perfusion imbalance, reduced lung compliance, and increasing symptoms. Early detection is possible by noting characteristic changes in gas exchange and chest radiograph. Awareness and early recognition of these changes, together with the predisposing clinical settings, can lead to the institution of appropriate therapy before patients become severely ill with frank alveolar pulmonary edema.     

Volume and time dependence of respiratory system mechanics in normal anaesthetized paralysed humans.

The purpose of the present investigation was to assess the effect of large tidal volumes and mean lung volumes on the viscoelastic properties of the respiratory system in normal humans; and to verify if in this case the results could be satisfactorily described by a simple linear viscoelastic model of the respiratory system. Twenty-eight subjects (7 females), aged 14-28 yrs, were studied before orthopaedic surgery on the lower limbs. None were obese, or had clinical evidence of cardiopulmonary disease. The interrupter conductance and the viscoelastic constants of the respiratory system were assessed using the rapid end-inspiratory airway occlusion method during mechanical ventilation with tidal volumes up to 3 L and applied end-expiratory pressures up to 23 cmH2O. It was found that the interrupter conductance increased linearly with lung volume over a larger range than used previously; and the viscoelastic resistance and time constant did not change over the entire range of tidal volumes and end-expiratory pressures studied. In conclusion, in normal anaesthetized, paralysed subjects a simple linear viscoelastic model satisfactorily described the viscoelastic behaviour of the respiratory system over the whole range of volume studied.     

Morphologic changes in lungs of anesthetized sheep following intravenous infusion of recombinant tumor necrosis factor alpha

Tumor necrosis factor alpha (TNF alpha) is a monokine released in response to endotoxin and has been suggested as a primary mediator of endotoxic shock. We have recently demonstrated that infusion of recombinant human tumor necrosis factor alpha (rTNF alpha) into sheep elicits a physiologic response in the lung that closely resembles endotoxemia. The present study examines the morphologic changes that accompany these alterations in pulmonary physiology. Five anesthetized, open-chest sheep received 0.01 mg/kg of protein (2.24 x 10(7) U rTNF alpha/mg) intravenously over 30 min. Lung biopsy tissue for light and electron microscopy was obtained from random lobes 7.5, 15, 30, 60, 120, 180, and 240 min after beginning the infusion. Pulmonary (Ppa) and systemic arterial pressures, cardiac output, and peripheral blood leukocyte number and differential counts were monitored throughout the study. Three control animals were treated in a similar manner but received either saline (n = 1) or rTNF alpha denatured by boiling for 30 min (n = 2). rTNF alpha caused an early increase in Ppa and peripheral blood leukopenia. Light microscopy revealed a threefold increase in the number of granulocytes per 100 alveolar profiles by 30 min and a fivefold increase by 2 h. From 60 min, increased alveolar wall thickness, red cell congestion, and peribronchovascular edema were apparent; from 2 h, there was increased cellularity of the alveolar walls and mononuclear cell infiltration of perivascular connective tissue. Electron microscopy revealed damage to alveolar Type I and II pneumonocytes and progressive endothelial injury from 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung volume maintenance prevents lung injury during high frequency oscillatory ventilation in surfactant-deficient rabbits

Controversy exists whether high frequency oscillatory ventilation with an active expiratory phase (HFO-A) should be used at low ventilator pressures or high alveolar volumes to minimize lung injury in the atelectasis-prone lung. We therefore ventilated 20 anesthetized, tracheostomized rabbits made surfactant-deficient by lung lavage in 1 of 3 ways: HFO-A at a high lung volume (HFO-A/HI), HFO-A at a low lung volume (HFO-A/LO), or conventional mechanical ventilation (CMV); all received 100% oxygen for 7 h. We examined oxygenation, lung mechanics, and lung pathology. Arterial oxygenation in the HFO-A/HI rabbits was kept greater than 350 mm Hg. Mean lung volume above FRC in these animals was 23.4 ml/kg. In rabbits ventilated with HFO-A/LO and CMV, arterial oxygen tensions were 70 to 100 mm Hg. Mean lung volumes were 7.8 and 4.3 ml/kg, respectively. Total respiratory system pressure-volume curves (P-V curves) showed no change from baseline in the HFO-A/HI group after 7 h of ventilation. The low lung volume groups (HFO-A/LO and CMV) showed a diminution in hysteresis of their P-V curves, lower total respiratory system compliance, more hyaline membranes and severe airway epithelial damage. (All changes significant with p less than 0.05). We conclude that maintenance of alveolar volume is a key mechanism in the prevention of lung injury during mechanical ventilation of the atelectasis-prone lung. For optimal outcome using high frequency oscillatory ventilation, alveoli must be actively reexpanded and then kept expanded using appropriate mean airway pressures.     

Elevated lung volume and alveolar pressure during jet ventilation of rabbits

We measured lung volume, tidal volume, and pressures at the airway opening, trachea, and alveoli during jet ventilation of rabbits at frequencies from 2 to 15 Hz when inspiratory time was varied from 10 to 50% of the ventilator cycle. Lung volume was determined dynamically and was dependent on tidal volume, expiratory duration, and the expiratory time constant of the respiratory system. Tidal volume decreased with increasing frequency and lung volume, and was greater than estimated dead-space volume over most of the frequency range studied. Pressure at the airway opening was not a good estimate of either mean pressure or pressure swings in the alveoli. Tracheal pressure corresponded fairly well to alveolar pressure. Alveolar pressure swings diminished with increasing frequency and decreasing inspiratory duration. In the clinical setting these results mean that measurement of pressures at the airway opening is not an adequate way to monitor patients during jet ventilation. In addition, the clinician must be aware that substantial increases in functional residual capacity may occur during jet ventilation, thereby placing the patient at risk of pneumothorax.     

Bronchopulmonary dysplasia in the adult

We describe 3 patients with adult respiratory distress syndrome that eventuated in a pathologic picture of honeycomb lung and a radiographic picture of variably cystic lung super-imposed on a background of diffuse alveolar infiltrates. All 3 patients had been treated with unusually high pressures of PEEP as well as high concentrations of oxygen for long periods of time (3 to 7 wk). Microscopically, the cystic structures in our patients appeared to be derived from collapse and fibrosis of the alveolar parenchyma with dilatation of the alveolar ducts. We suggest that this process is morphologically and radiographically similar to bronchopulmonary dysplasia as seen in the newborn.     

Physiologic and histologic determinants of gas exchange during induction of oleic acid pulmonary edema

Five anesthetized mongrel dogs were studied during the induction of acute oleic acid pulmonary edema to determine the influence of cardiac output (Qt), extravascular lung water (ETV), and the degree of alveolar flooding on pulmonary gas exchange. Qt and ETV were measured by thermal dye dilution techniques, alveolar flooding was assesed by histologic studies, and gas exchange was quantitated by the multiple inert gas elimination technique (MIGET). Estimates of the inert gas venous admixture [(Qva/Qt) IG%] were obtained at different experimental stages from the MIGET data to provide an index of overall gas exchange impairment. Pulmonary edema was produced by the intravenous (IV) infusion of oleic acid (0.08 mL/kg). Measurements of Qt, ETV and (Qva/Qt) IG% were made prior to lung injury and at 40, 80, and 120 minutes after injury. After death the lungs were inflated and frozen. Thirty cores of lung parenchyma (2 mL each) were obtained for histologic assessment of alveolar flooding. In the early phase of edema formation (0 to 80 minutes), (Qva/Qt) IG% increased as ETV increased. After 80 minutes, ETV stabilized and further changes in (Qva/Qt) IG% were then primarily determined by changes in Qt (r = .94). The histologically assessed degree of alveolar flooding correlated well with ETV at the 120-minutes stage (r = .85). However, by use of multivariate analysis, the addition of the histologic information did not appreciably improve the prediction of gas exchange in acute oleic acid pulmonary edema.     

Mechanical ventilation-induced air-space enlargement during experimental pneumonia in piglets

Mechanical ventilation-induced air-space enlargement was investigated in a porcine model of multifocal pneumonia. Following the intrabronchial inoculation of Escherichia coli, 9 piglets (22 +/- 2 kg) were ventilated with a tidal volume (VT) of 15 ml/kg for 43 +/- 15 h. Five noninoculated piglets ventilated for 60 h with the same VT served as control animals. Following death, the lungs were fixed and lung morphometry was assessed. In inoculated animals, unventilated infected and normally ventilated noninfected pulmonary lobules coexisted. In normally ventilated lung regions (1) emphysema-like lesions were present, (2) mean alveolar area and mean linear intercept were significantly greater in inoculated than in control animals, and (3) the degree of alveolar distension correlated with the decrease in respiratory compliance. In unventilated lung areas (1) pseudocysts were frequent, (2) alveolar edema was rare, (3) bronchiolectasis was frequent, (4) mean bronchiolar area was greater in inoculated than in control animals, and (5) the degree of bronchiolar distension correlated with the increase in inspiratory plateau pressure. In conclusion, in piglets with severe bronchopneumonia, air-space enlargement rather than pulmonary edema was the major feature of mechanical ventilation-induced lung barotrauma and resembled lesions previously reported in critically ill patients ventilated using high inspiratory pressures.     

Expiratory mechanics before and after uncomplicated heart surgery

In 12 mechanically ventilated anesthetized paralyzed patients undergoing cardiac surgery for either coronary bypass or for correcting valvular dysfunction volume, airflow, tracheal, esophageal, and transpulmonary pressures were measured. Respiratory system elastance and resistance were partitioned into their lung and chest wall components throughout tidal relaxed expiration. Measurements were performed prior to thoracotomy and just after rib cage closure. Before surgery, patients with valvular disease had significantly higher respiratory system and lung elastances and resistances than those with ischemic heart disease. After surgery, patients with valvular disease showed a decrease in respiratory system and lung resistances. Surgery strikingly modified chest wall resistive properties in both groups. Postoperatively, the mechanical properties of the respiratory system were very similar in valvular and ischemic patients.     

Elastic properties of the lung and the chest wall in young and adult healthy pigs.

Understanding of the elastic pressure/volume (Pel/V) curve is still limited in health and disease. The aim of the present study was to elucidate the Pel/V curve and elastance of the respiratory system (ERS) lung (EL) and chest wall (ECW) in healthy pigs. Six young (20.8 kg) and seven adult (58.9 kg), anaesthetized, paralysed and ventilated pigs were studied. Pel/V curves were recorded at zero end-expiratory pressure (ZEEP) and at positive end-expiratory pressure (PEEP) up to 40 cmH2O with a computer controlled ventilator during an insufflation at a low, constant flow. Pel/V curves of the respiratory system showed a complex pattern in both young and adult pigs. During the insufflation, ERS decreased, increased, fell, and increased again. A second Pel/V curve recorded immediately after the first one showed lower elastance and only one early fall in ERS. ECW fell over the initial segment and was then nearly stable. Difference between 1st and 2nd curves reflected changes in EL caused by recruitment during the 1st insufflation. At PEEP, such signs of collapse and recruitment were reduced. A strong tendency to lung collapse contributes to a complex pattern of elastic pressure/volume curves. At low volumes and distending pressures the chest wall contributes significantly to changes in respiratory system elastance.     

Effect of edema on segmental vascular resistance in isolated lamb lungs determined by micropuncture

We have studied the mechanical effects of fluid accumulation on the pulmonary vasculature in 28 isolated blood perfused lungs of newborn lambs. Vascular resistance in the pulmonary arteries, microvessels, and veins was determined by micropuncture measurement of microvascular pressures, and regional distribution of blood flow in the lungs was determined using radiolabelled microspheres both before and after the development of varying degrees of hydrostatic edema. Edema was induced by raising venous pressure. During measurements, alveolar and venous pressures were kept constant at 7 and 8 cm H2O, respectively, as well as lung blood flow (540 +/- 107 ml/min). All vascular pressures were referenced to the superior surface of the lung, site of all micropunctures. Active vasomotor changes were eliminated by addition of papaverine to the perfusate. Under baseline nonedematous conditions in the absence of vasomotor tone, 17% of the total pressure drop was in arteries, 41% was in microvessels, and 42% was in veins. With the development of alveolar edema (80 +/- 13% weight gain), there was no change in total or segmental vascular resistance, but after 148 +/- 97% weight gain, total pulmonary vascular resistance increased by 74%. Segmental pressure drop increased in arteries by 172% and in microvessels by 132% but decreased by 22% in the venous segment. Regional distribution of blood flow remained unchanged. Possible mechanisms for increased resistance to blood flow may be compression of small arterioles and venules (less than 20 micron diameter) by liquid cuffs and/or occlusion of microvessels by the weight of alveolar liquid.