Minimize Lung Injury Research Articles

Bronchopulmonary dysplasia: an enduring challenge.

1. Yvonne E. Vaucher, MD, MPH* 1. *Clinical Professor of Pediatrics, Division of Neonatology, University of California, San Diego, Calif. After completing this article, readers should be able to: 1. Describe the most common cause of chronic lung disease during infancy. 2. Explain the importance of a history of bronchopulmonary dysplasia throughout childhood. 3. Identify infants at high risk for developing bronchopulmonary dysplasia. 4. List the adverse effects associated with postnatal corticosteroids. Despite clinical advances in antepartum, intrapartum, and neonatal care, bronchopulmonary dysplasia (BPD) continues to challenge infants who have been in neonatal intensive care units and their caretakers. BPD is the most common cause of chronic respiratory disease during infancy and remains a major cause of long-term medical, pulmonary, and neurodevelopmental morbidity, increasing the cost of health care and the utilization of medical and educational resources throughout childhood. BPD is a clinical diagnosis, defined by oxygen dependence for a specific period of time after birth and accompanied by characteristic radiographic findings that correspond to anatomic abnormalities. Thus far, a precise physiologic definition of BPD is lacking. As the clinical presentation has evolved over the past 30 years, so has the definition. As originally described by Northway in the 1960s, the diagnosis of classic BPD was based on progressive radiographic changes in preterm infants who were treated for severe respiratory distress syndrome (RDS) immediately after birth and had prolonged ventilator and oxygen dependence. This form of BPD occurred in larger, relatively mature preterm infants, who required treatment with high-pressure mechanical ventilation and high concentrations of oxygen. Although the acute respiratory disease initially improved in these infants, oxygen requirements increased 7 to 10 days after birth and persisted for at least 28 days. The definition of BPD subsequently was modified by Bancalari to include preterm infants who had less severe RDS that initially required short-term mechanical ventilation, but who also developed persistent respiratory symptoms and an oxygen requirement for at least 28 days after birth …

Decreased indicators of lung injury with continuous positive expiratory pressure in preterm lambs.

Continuous positive airway pressure (CPAP) is being used clinically to avoid mechanical ventilation of preterm infants as a strategy to minimize lung injury. There is little experimental information about how CPAP might minimize lung injury after preterm birth. We induced preterm labor in antenatal glucocorticoid-treated sheep carrying twins at 133 d gestation with an inhibitor of progesterone synthesis. The lambs delivered spontaneously approximately 2 d later and were randomized to three groups: no ventilation (n = 4), conventional mechanical ventilation to a target PCO(2) of 40 mm Hg (n = 5), or CPAP using a bubble CPAP device set to deliver 5 cm H(2)O pressure (n = 6). The CPAP lambs breathed without distress and maintained PCO(2) values of approximately 60 mm Hg. At 2 h of age, the lungs of the CPAP lambs held 74 +/- 4 mL/kg air at 40 cm H(2)O pressure, which was more than the 60 +/- 3 mL/kg for the ventilated lambs (p < 0.05). Lymphocyte and monocyte numbers in alveolar washes were equivalent in the unventilated, ventilated, and CPAP lambs. However, no neutrophils were found in the unventilated lambs, and the ventilated lambs had 6.6 times more neutrophils in alveolar washes than did the CPAP lambs (p < 0.05). The cells in alveolar wash from CPAP lambs contained less hydrogen peroxide than did the cells from ventilated lambs (p < 0.05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life.

Decreased Indicators of Lung Injury with Continuous Positive Expiratory Pressure in Preterm Lambs

Continuous positive airway pressure (CPAP) is being used clinically to avoid mechanical ventilation of preterm infants as a strategy to minimize lung injury. There is little experimental information about how CPAP might minimize lung injury after preterm birth. We induced preterm labor in antenatal glucocorticoid-treated sheep carrying twins at 133 d gestation with an inhibitor of progesterone synthesis. The lambs delivered spontaneously approximately 2 d later and were randomized to three groups: no ventilation (n = 4), conventional mechanical ventilation to a target Pco2 of 40 mm Hg (n = 5), or CPAP using a bubble CPAP device set to deliver 5 cm H2O pressure (n = 6). The CPAP lambs breathed without distress and maintained Pco2 values of approximately 60 mm Hg. At 2 h of age, the lungs of the CPAP lambs held 74 ± 4 mL/kg air at 40 cm H2O pressure, which was more than the 60 ± 3 mL/kg for the ventilated lambs (p < 0.05). Lymphocyte and monocyte numbers in alveolar washes were equivalent in the unventilated, ventilated, and CPAP lambs. However, no neutrophils were found in the unventilated lambs, and the ventilated lambs had 6.6 times more neutrophils in alveolar washes than did the CPAP lambs (p < 0.05). The cells in alveolar wash from CPAP lambs contained less hydrogen peroxide than did the cells from ventilated lambs (p < 0.05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life.

Impact of Mechanical Ventilation on the Developing Airway

After completing this article, readers should be able to: 1. Explain why immature infants are at a greater risk for mechanical ventilation-induced airway damage than are more mature infants. 2. Describe the effect of ventilatory pressures on components of the airway. 3. Delineate how mechanical ventilation disrupts airway mechanics. 4. Characterize how mechanical ventilation affects immature airway smooth muscle. 5. Describe techniques of optimizing ventilation to minimize respiratory damage. Although the air passages take on a mature appearance well before a fetus is viable, they undergo significant maturational changes in late gestation. During development, the airways are more susceptible to damage. In fact, although controversy still surrounds the pathogenesis of bronchopulmonary dysplasia (BPD) and other neonatal airway complications, it appears that the duration and higher pressures of mechanical ventilation, along with the use of oxygen, are related to the development of airway-related problems in preterm infants. As a result, because of their greater need for ventilatory assistance, very preterm infants are at substantially increased risk of airway damage. With recent and continuing advancements in neonatal care, a growing number of immature infants survive premature births. One of the primary hurdles that must be overcome in these infants is respiratory system immaturity. In this context, an understanding of the embryologic development and physiologic maturation of the respiratory system is imperative. The respiratory system can be subdivided grossly into the airways and the lung parenchyma. Developmental changes in the mechanical properties of these two components predispose the immature airway to injury. The immature lung is a relatively noncompliant structure. During neonatal development, lung compliance increases with lung maturity. However, the opposite is true for airways. Immature airways are relatively more compliant than their mature counterparts, with airway maturation resulting in a decrease in airway compliance. This produces an interesting predicament when contemplating the administration of mechanical ventilation …

Lung recruitment during small tidal volume ventilation allows minimal positive end-expiratory pressure without augmenting lung injury.

Ventilation with positive end-expiratory pressure (PEEP) above the inflection point (P(inf)) has been shown to reduce lung injury by recruiting previously closed alveolar regions; however, it carries the risk of hyperinflating the lungs. The present study examined the hypothesis that a new strategy of recruiting the lung with a sustained inflation (SI), followed by ventilation with small tidal volumes, would allow the maintenance of low PEEP levels (<P(inf)) without inducing additional lung injury. Prospective, randomized, controlled ex vivo study. An animal laboratory in a university setting. Isolated nonperfused lungs of adult Sprague-Dawley rats. We studied the effect on compliance and lung injury in four groups (n = 10 per group) of lavaged rat lungs. One group (group 1) served as a control; their lungs were inflated at PEEP < P(inf) but not ventilated. The other three groups were ventilated with small tidal volumes (5 to 6 mL/kg) for 2 hrs with the following interventions: group 2, PEEP < P(inf) without SI; group 3, PEEP < P(inf) after a SI to 30 cm H2O for 30 secs; and group 4, PEEP > P(inf). In groups 2 and 4, static compliance decreased after ventilation (p < .01). Histologically, group 2 (PEEP < P(inf) without SI) showed significantly greater injury of small airways, but not of terminal respiratory units, compared with group 1. Group 3 (PEEP < P(inf) after a SI), but not group 4, showed significantly less injury of small airways and terminal respiratory units compared with group 2. We conclude that small tidal volume ventilation after a recruitment maneuver allows ventilation on the deflation limb of the pressure/volume curve of the lungs at a PEEP < P(inf). This strategy a) minimizes lung injury as well as, or better than, use of PEEP > P(inf), and b) ensures a lower PEEP, which may minimize the detrimental consequences of high lung volume ventilation.

SOLUBLE TRANSITION METALS MEDIATE RESIDUAL OIL FLY ASH INDUCED ACUTE LUNG INJURY

Identification of constituents responsible for the pulmonary toxicity of fugitive combustion emission source particles may provide insight into the adverse health effects associated with exposure to these particles as well as ambient air particulate pollution. Herein, we describe results of studies conducted to identify constituents responsible for the acute lung injury induced by residual oil fly ash (ROFA) and to assess physical-chemical factors that influence the pulmonary toxicity of these constituents. Biochemical and cellular analyses performed on bronchoalveolar lavage fluid obtained from rats following intratracheal instillation of ROFA suspension demonstrated the presence of severe inflammation, an indicator of pulmonary injury, which included recruitment of neutrophils, eosinophils, and monocytes into the airway. A leachate prepared from ROFA, containing predominantly Fe, Ni, V, Ca, Mg, and sulfate, produced similar lung injury to that induced by ROFA suspension. Depletion of Fe, Ni, and V from the ROFA leachate abrogated its pulmonary toxicity. Correspondingly, minimal lung injury was observed in animals exposed to saline-washed ROFA particles. A surrogate transition metal sulfate solution containing Fe, V, and Ni largely reproduced the lung injury induced by ROFA. Metal interactions and pH were found to influence the severity and kinetics of lung injury induced by ROFA and soluble transition metals. These findings provide direct evidence for the role of soluble transition metals in the pulmonary injury induced by the combustion emission source particulate, ROFA.

Surfactant protein-B and lung function in surfactant-treated preterm lambs.

We asked if the amount of SP-B (range 37-410 micrograms/ml) in surfactants used to treat preterm lambs at 123 days of gestation correlated with postnatal lung function or the SP-B content of surfactant recovered by alveolar washes after 10 h ventilation. Ventilation was initiated using a low tidal volume strategy to minimize early lung injury. There were small increases in compliance for the lambs treated with surfactants containing more than 37 micrograms/ml SP-B and an increased lung volume for lambs treated with a surfactant containing 385 micrograms/ml/ml relative to the surfactant containing 37 micrograms/ml SP-B. The amount of SP-B in the surfactant used for treatment correlated linearly with the amount of SP-B in the surfactant recovered from the lambs (r = 0.95, p < 0.001). Albumin leak from the vasculature to the airspace was low as was total protein in alveolar washes, indicating minimal lung injury. The SP-B content of surfactant (from 37 to 410 micrograms/ml) had minimal effects on postnatal lung function over a 10-hour study period in lambs ventilated in a manner to minimize lung injury.

Keratinocyte growth factor reduces lung damage due to acid instillation in rats.

Acid aspiration is a serious complication of anesthesia and other forms of unconsciousness that can result in the adult respiratory distress syndrome (ARDS), which continues to have a very high mortality despite our current therapeutic interventions. This type of injury damages the alveolar epithelium, principally alveolar type I cells, and requires proliferation of alveolar type II cells to restore gas exchange units. Since keratinocyte growth factor (KGF) has been shown to be a potent mitogen for alveolar type II cells, we evaluated whether intrabronchial administration of KGF would minimize lung injury due to the unilateral instillation of 0.1 N hydrochloric acid (HCl). Rats were pretreated or post-treated by intrabronchial instillation of KGF (5 mg/kg) into the left lung before HCl instillation. All rats receiving KGF at 48 or 72 h before HCl instillation survived for the 7-day observation period, whereas the mortality rate for those receiving HCl alone or saline followed by HCl was 31% and 33%, respectively. Pretreatment with KGF at 72 h but not at 24 or 48 h considerably ameliorated morphologic damage produced by HCl. Inflammatory cells in bronchoalveolar lavage were markedly decreased 3 and 7 days after HCl instillation by the 72-h KGF pretreatment. Pretreatment with KGF at 72 h also attenuated the reduction of total lung capacity, decreased the alpha 1(I) procollagen mRNA levels, and diminished hydroxyproline accumulation due to HCl instillation. Saline pretreatment at 72 h had no significant effect on the HCl injury and subsequent physiologic abnormalities. Our attempts to improve outcome with post-treatment instillation of KGF were unsuccessful. We conclude that KGF pretreatment reduces lung injury due to acid instillation and can prevent subsequent pulmonary fibrosis.

Dexamethasone therapy in chronic lung disease.

Steroids have been used in the treatment of infants with chronic lung disease (CLD) for over a decade. Some studies have reported beneficial effects from long, tapering 42-day course of dexamethasone. Short term regimens have also shown beneficial effects on ventilator dependent infants with CLD. Although steroid therapy has been successful in infants with established CLD, more recently, dexamethasone therapy is being initiated in infants with RDS considered to be at risk for developing CLD. Some of the initial studies reported higher rates of infection, but more recent prospective data have not shown an increased incidence of sepsis in patients treated with steroids. Presently, early steroid therapy appears to be beneficial to minimize lung injury in infants treated with surfactant.

Predictors of survival for infants with congenital diaphragmatic hernia

Over the past decade, the survival rate of infants with congenital diaphragmatic hernia (CDH) treated in the intensive care unit of the Royal Children's Hospital, Melbourne, has remained unchanged at 56% ± 6%. Newer forms of treatment, such as extracorporeal membrane oxygenation (ECMO), high-frequency oscillation, and surfactant and nitric oxide therapy, are now available. The exact role of these therapies in the management of infants with CDH has not been determined. This study examines five clinical parameters derived from an infant's best preoperative ventilatory and blood gas data in the first 24 hours of life. One hundred twenty-five CDH infants were admitted to the intensive care unit between January 1, 1981 and December 31, 1991. Criteria for inclusion in the study were (1) CDH diagnosed within 6 hours of delivery, (2) ventilation before repair, and (3) no associated lethal congenital abnormality. Of the 90 cases studied in detail, there were 38 deaths (42% mortality rate). All five parameters were analyzed by receiver operating curve analysis to determine the optimum value of each parameter in predicting survival. An oxygenation index ( MAP × Fio 2 Pao 2 ) of less than 0.08 predicted a 94% chance of survival, with a sensitivity of 96% and a specificity of 95%. Similarly, a modified ventilation index ( PIP × RR × CO 2 1,000 ) of less than 40 predicted a 91% chance of survival, with a sensitivity of 94% and a specificity of 86%. By stratifying each criterion according to outcome, three groups of infants were identified according to their response to conventional therapy. There is a large group of infants that can be expected to survive with conventional therapy and are likely to have minimal pulmonary hypoplasia. A second group can be expected to die with use of conventional therapy; this group may well represent infants with severe pulmonary hypoplasia who are unlikely to benefit from therapies designed to combat pulmonary hypertension or minimize lung barotrauma. Between these two groups is a small group of infants whose outcome from conventional therapy is less predictable. We believe that this group may represent infants with significant pulmonary hypertension and moderate pulmonary hypoplasia. These patients may benefit from newer therapies that treat pulmonary hypertension and minimize lung injury.

Pathogenesis of Respiratory Failure in the Preterm Infant

Respiratory failure in the preterm results from not only surfactant deficiency but also the immaturity of a number of other elements that have a structural basis. Airway, alveolar, fluid clearance, and epithelial and endothelial barrier functions also are important to lung function. Immaturities in these lung elements have identifiable adverse consequences for lung function such as pulmonary interstitial emphysema and pulmonary edema. The maturation of each of these elements appears to be achievable by agents such as corticosteroids, and maturation will result in an improved response to surfactant treatments. While surfactant treatments can improve respiratory failure by minimizing lung injury, other aspects of lung immaturity continue to contribute to respiratory compromise in the preterm. A thorough understanding of respiratory failure in the newborn depends on a better appreciation of the contribution of immaturity of the different structural elements of the lung on lung function.

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.

A serial immunologic and histopathologic study of lung injury induced by trimellitic anhydride.

Trimellitic anhydride (TMA) can induce immunologic lung disease in exposed workers. We have developed a rat model of TMA lung injury characterized by lung hemorrhage and an immune response to trimellityl (TM) haptenized lung proteins. The model is similar to the pulmonary disease-anemia syndrome (PDA) seen in workers exposed to TMA fumes. Sprague-Dawley rats, 15 per exposure period, inhaled micronized TMA powder, 100 micrograms/m3, 6 h/day, for 2,6, or 10 days and were sacrificed. At each time period, total, IgG, IgA, and IgM antibody to TM-rat serum albumin (TM-RSA) were measured by radiolabeled antigen binding and enzyme-linked immunosorbent assay (ELISA) in serum and bronchoalveolar lavage fluid (BAL). Hemorrhagic lung foci, weight, and displacement volume were determined, and lungs were examined by light and electron microscopy. There was no lung injury or antibody response at 2 days. There was minimal lung injury at 6 days with low levels of antibody in BAL and serum. At 10 days, there was a marked increase in hemorrhagic foci and in BAL and serum antibody levels. BAL antibody levels at 6 and 10 days had higher correlations with measures of lung injury than corresponding serum levels. There was minimal ultrastructural change at 6 days. By Day 10, there was marked intraalveolar hemorrhage, alveolar septal inflammatory nodules, abundant alveolar macrophages, and evidence of endothelial and epithelial cell injury. These results indicate that the immune response to inhaled TMA occurs parallel with the development of lung lesions, and antibody levels in BAL and serum are highly correlated with lung injury.

Response of mouse lung to crocidolite asbestos. 1. Minimal fibrotic reaction to short fibres.

To determine the relationship between the development of pulmonary fibrosis and the size of deposited asbestos, we prepared a pure sample of short crocidolite fibres and instilled 0.5 mg of 0.1 mg to the lungs of mice. Animals were killed up to 20 weeks later with 3H thymidine injected 1 h before death. By bronchoalveolar lavage, there was a rapid transient increase in polymorph neutrophils (PMN) and in glucosaminidase levels; alveolar macrophage (AM) numbers were elevated in the 0.5 mg group for eight weeks. Most fibres were phagocytized by AM, many of which were heavily laden and cleared from the lung over the 20 week period. Some fibres were seen in type 1 epithelial cells, frequently associated with cell injury. From cell kinetic studies, a very brief proliferative response was seen in bronchiolar epithelial and Type 2 alveolar epithelial cells. A greater response was seen in interstitial fibroblasts which showed increased labelling up to two weeks after 0.5 mg asbestos. However no granulomas were seen and very little fibrosis was found by morphology or by biochemistry at any time after 0.5 mg; no fibrosis was seen after instilling 0.1 mg. The results show that a high dose of exclusively short asbestos fibres produces minimal lung injury and fibrosis in spite of long standing macrophage-fibre interaction in the alveoli.

A new elastase inhibitor from Streptococcus pneumoniae protects against acute lung injury induced by neutrophil granules.

A neutrophil elastase-inhibitor isolated from lysed pneumococcal cells, as well as trypsin-digest peptides derived from this factor, were tested for their ability to suppress acute lung injury in mice treated with human neutrophil granule extracts. Injury was assessed by measuring pulmonary sequestration of circulating 125I-labeled albumin, lung water, and lung hemoglobin. Both the native inhibitor and the tryptic-peptides gave good protection when preincubated with granule extract for brief periods before intrapulmonary instillation. Lesser, but still significant, protection was observed in the absence of preincubation. Protection was not simply due to addition of exogenous proteins to the granule extract because substitution of goat immunoglobulin for pneumococcal fraction was ineffective. These results suggest that pneumococcal elastase-inhibitors, recently described by us, may play a role in minimizing lung injury during pneumococcal pneumonia.

The Measurement of Lung Water Content

It is clear that lung water content or things related to lung water content can be measured. The major question is whether useful information will be obtained to make development worthwhile. In my experimental laboratory we have used, then abandoned, the measurement of lung water content in life by various techniques. We have special needs, of course, for very sensitive methods which will detect minimal injury and very small changes in lung water content. In the clinic, however, this may not be so serious a limitation, although one is always endeavoring to achieve diagnosis of minimal injury and minimal edema. Although static methods for measuring lung water content are available in profusion, none has been proven to be more useful than the chest roentgenogram. Kinetic methods are being developed which have the potential of being sensitive to minimal lung injury, such as leads to edema.

THE PHYSIOLOGY OF LEAKY LUNGS

This paper outlines the relationships between the structures and functions of the pulmonary epithelium and endothelium, and describes some new methods for measuring their permeability in a variety of experimental and clinical situations. Much of the work outlined in this paper is reviewed by Davies (1973), Staub (1974, 1978, 1981), Effros (1978), Staehelin and Hull (1978), Diana and Fleming (1979), and Chinard (1980). Diffuse injury of the alveolar epithelium and the pulmonary vascular endothelium may follow aspiration of gastric contents, inhalation of toxic smokes and vapours or pulmonary embolism. Similar damage may occur when the complement system is activated during haemodialysis and after trauma or infection (Hammerschmidt et al., 1980). Complement activation has also been reported after cardiopulmonary bypass (Chenoweth et al., 1981) but no correlation was found between activation and changes in arterial oxygen tension. If any injury does occur it may cause these layers to become unduly leaky to water and solute. If the injury creates holes in the epithelium large enough to leak protein then pulmonary oedema will ensue, but if the leakage is minimal and confined to small molecular weight solutes there is no clinically obvious effect. A major problem in establishing the link between a potentially damaging stimulus and this minimal pulmonary response has been the lack of an objective test to measure a deterioration in function of the vascular endothelium and, in particular, the epithelial lining of the airways and alveoli. Measurements of changes in lung mechanics or gas exchange are either non-specific or too insensitive to draw any conclusions about the functional effects of this minimal lung injury. One approach could examine the effect of lung injury on pulmonary metabolism (Said, 1979) but, so far, little is known about the