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The use of perfluorochemical (PFC) liquids to facilitate or support respiration has been under study for several decades. The low surface tension and high respiratory gas solubility of liquid PFC enable adequate oxygenation and carbon dioxide removal at low insufflation pressures relative to gas ventilation in the immature or injured lung. Because liquid ventilation homogeneously inflates the lung and improves V/Q matching it has been studied as a vehicle for delivering biologically active agents to the lung tissues and systemic circulation. More recently, we have shown the utility of highly opaque PFC liquids as a high resolution computed tomographic (HRCT) bronchographic contrast agent either during LV or gas breathing after tracheal instillation of small quantities of PFC. As a result of extensive experimental work in premature animals as well as lung injury models, liquid PFC ventilation has been recently implemented as an investigational therapy for severe respiratory distress in human infants. This manuscript summarizes the physiological principles and applications of LV as well as the results of initial investigational clinical studies in human neonates with severe respiratory distress.

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To evaluate the effect of the physical properties of density and viscosity on airway resistance, three perfluorochemical fluids (PFCs) were used: FC-75, Liquivent, and APF-140. Using two different endotracheal tubes (ETT) (3.0mm ID and 4.0mm internal diameter (ID)), the three fluids were studied at steady state flow conditions over a range that approximated peak flow required for liquid ventilation of neonatal lambs (0.005-0.02 l/sec). The slope of airway resistance (Raw)-flow curves and absolute values of Raw for the 3 PFC liquids were higher for the 3.0 ETT compared to the 4.0 ETT. The 3.0 ETT demonstrated resistance changes that were dependent on flow, density and viscosity. The 4.0 ETT showed a resistance-flow relationship that was relatively less dependent on flow, density and viscosity.

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The use of neat perfluorochemical liquid (PFC) as an alternative respiratory medium has gained increasing attention for assessment and treatment of the immature or injured lung. In vitro and in vivo plain film and computed tomographic (CT) studies were performed on small and large animals to evaluate the use of perfluorooctylbromide (perflubron) as a bronchographic contrast agent and to quantitate the distribution and elimination of this fluid from the lung following total liquid ventilation or during gas breathing after tracheal instillation of small quantities of this liquid. The results demonstrate the utility of a highly radiopaque PFC liquid in combination with diagnostic imaging techniques to visualize small airways anatomy, identify regional and gravity dependent differences in distribution/elimination of the fluid, ventilation, and track PFC liquid following therapeutic application.

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The present study was designed to evaluate the effect of a perfluorocarbon erythrocyte substitute on hemodynamics in the newborn lamb. Isovolumic double volume exchange transfusions were performed with perfluorocarbon emulsion (FC-43) on lambs who were ventilated to maintain normal acid base status. Hematocrit, fluorocrit, viscosity, arterial gas tensions, mean arterial pressure, and heart rate were determined before (control) and after (exchange) exchange transfusion. A radiolabeled microsphere technique was used and cardiac output, organ blood flow, organ vascular resistance, and oxygen delivery were calculated. As the hematocrit and viscosity decreased and the fluorocrit increased, there was a significant increase in PaO2 as well as a significant decrease in A-a gradient and oxygen content. There was no significant change in the acid-base status or the hemodynamic profile (heart rate, stroke volume, cardiac output, and mean arterial pressure). Blood flow to the heart and brain showed a significant increase, whereas flow to the cortex of the kidney showed a significant decrease. There was no significant change in flow to the gastrointestinal tract. Organ vascular resistance in the brain significantly decreased, increased in the kidney, and showed no significant change in the heart and gastrointestinal tract. Oxygen delivery significantly decreased in all organs except the heart. These data suggest that perfluorocarbon emulsions can acutely maintain hemodynamic stability in the newborn lamb and that the intrinsic properties of perfluorocarbons allow for the preservation of adequate oxygenation and acid-base status.

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In the clinical setting, nasal cannulas are frequently used to deliver supplemental oxygen to neonates and are not believed to affect the general respiratory status. In contrast, it was hypothesized that clinical changes associated with nasal cannula gas flow may be related in part to the generation of positive end-distending pressure. To test this hypothesis, alterations in esophageal pressure were quantified as an indication of end-distending pressure and thoracoabdominal motion was quantified as an indication of breathing patterns in 13 preterm infants at gas flow levels of 0.5, 1, and 2 L/min delivered by nasal cannula with an outer diameter of either 0.2 or 0.3 cm. Changes in esophageal pressure were assessed by esophageal balloon manometry. Ventilatory patterns were assessed from thoracoabdominal motion by using respiratory inductive plethysmography. Thoracoabdominal motion was quantitated as a phase angle (theta); larger values represent greater asynchrony. The 0.2-cm nasal cannula did not deliver pressure or alter thoracoabdominal motion at any flow. In contrast, the 0.3-cm nasal cannula delivered positive end-distending pressure as a function of increasing levels of gas flow (r = .92) and reduced thoracoabdominal motion asynchrony. The mean pressure generated at 2 L/min was 9.8 cm H2O. These data demonstrate that nasal cannula gas flow can deliver positive end-distending pressure to infants and significantly alter their breathing strategy. This finding raises important concerns about the indiscriminate therapeutic use, size selection, and safety of nasal cannulas for the routine delivery of oxygen in preterm infants.

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To determine whether changes in lung volume may be responsible for the clinical improvement in preterm infants given exogenous surfactant, we measured functional residual capacity (FRC), lung mechanics, and partial pressure of oxygen in seven ventilated neonates (birth weight 1080 +/- 361 gm (mean +/- SD); gestational age 28.3 +/- 2.6 weeks) less than 9 hours of age who had findings typical of hyaline membrane disease. All patients received 100 mg/kg calf lung surfactant extract. FRC was measured by a closed-circuit helium-dilution technique, and lung mechanics were determined by least mean squares analysis. FRC increased in all patients (range 56% to 330%; p less than 0.03). Dynamic lung compliance and total airway conductance did not change. Mean +/- SEM specific lung compliance (dynamic lung compliance/FRC) decreased 55.93% +/- 4.27% (p less than 0.02) and mean specific conductance (total airway conductance/FRC) decreased 45.91% +/- 9.74% (p less than 0.009). Mean alveolar/arterial partial pressure of oxygen ratio decreased 51.0% +/- 8.67% (p less than 0.01). These data indicate that the immediate improvement in oxygenation after surfactant administration is related to increased lung volumes. The decrease in specific lung compliance and specific airway conductance is suggestive of increased distention rather than recruitment of functional alveoli.

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This report details the application of liquid perfluorochemical ventilation for investigational therapy in three human preterm neonates (gestational ages 28, 24, and 23 weeks) in whom conventional therapies for severe respiratory distress had failed. Liquid ventilation was performed without difficulty in each infant for two 3- to 5-minute cycles by means of gravity-assisted technique. Marked improvement in lung distensibility, without a change in cardiovascular status, occurred in all three infants after liquid ventilation; oxygenation improved in two. All infants died within 19 hours of liquid ventilation, and there was no evidence of retained perfluorochemical fluid in the lungs or pleural space. Death was probably related to the severity of lung disease before the initiation of liquid ventilation. This satisfactory initial outcome shows the feasibility and potential of this treatment of pulmonary dysfunction in the preterm neonate.

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Thoracoabdominal asynchrony (TAA) has long been thought clinically useful in the assessment of airflow obstruction (AO) in infants. To test the hypothesis that the measurement of TAA is useful in the assessment of lung mechanics in infants with AO, we have used respiratory inductive plethysmography (RIP) to quantity TAA. We compared changes in TAA to changes in lung mechanics before and after aerosolized bronchodilator (BD) administration in 13 infants. Abdominal wall (AB) and rib cage (RC) motion were displayed on an X-Y recorder in a Lissajous figure. Asynchrony between RC and AB motion was quantified by comparing the width m of the Lissajous figure (difference between AB inspiratory and expiratory positions) at mid-RC excursion with the total AB excursion at its extremes (s). Phase angle phi ws computed as sin phi = m/s (or phi = 180 degrees - mu, where sin mu = m/s for phase angles greater than 90 degrees) and was taken as a measure of TAA. Lung resistance RL and elastance EL were calculated from esophageal pressure (Pes), mouth pressure, tidal volume, and tidal flow. All infants displayed TAA at baseline. After BD administration, TAA decreased in those infants in whom RL decreased. The percentage decrease in the phase angle from baseline after BD administration was significantly correlated with the decrease in peak-to-peak Pes (delta Pes) and the percentage decrease in RL and EL. We conclude that AO in infants leads to TAA through altered pleural pressure swings acting on the compliant chest wall. Changes in lung mechanics induced by bronchodilators are reflected in changes in TAA.(ABSTRACT TRUNCATED AT 250 WORDS)

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Response to bronchodilator (BD) and chest physical therapy (CPT) was evaluated in newly diagnosed infants with cystic fibrosis (n = 13; age, 6.9 +/- 1.5 SE months) who were asymptomatic for lung disease at the time of the study. Lung function was assessed from the mechanics and energetics of breathing prior to and following combined BD and CPT. After therapy, respiratory rate, tidal volume, minute ventilation, and pulmonary compliance were not statistically different from values under baseline conditions. In contrast, there was a significant decrease in pulmonary resistance (-34%; P less than 0.05) and the resistive work of breathing (-26%; P less than 0.05) following the combined treatment. The effect of combined BD and CPT in decreasing the resistive respiratory load may be related to relief of subclinical bronchospasm, reduction in mucosal edema, and mobilization of mucous secretions.

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The mechanics and energetics of breathing were studied in preterm infants with bronchopulmonary dysplasia while spontaneously breathing control gas and helium-oxygen (Heliox) gas mixtures. During Heliox breathing, there was a significant decrease in pulmonary resistance, resistive work of breathing, and mechanical power of breathing, whereas ventilation remained unchanged. Breathing a lower density gas mixture (Heliox) may have therapeutic value by decreasing the demands on the respiratory muscles and the caloric requirements for breathing. Therefore, this modality may reduce potential respiratory muscle fatigue and avail additional calories for growth and recovery in the preterm infant with bronchopulmonary dysplasia.

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To investigate the acute physiologic effects of external expiratory resistance on lung function in extubated neonates recovering from respiratory disease, lung mechanics, respiratory patterns, and functional residual capacity were measured in ten neonates dueing a control period and immediately after application of an external expiratory resistance of 30 cm H2O/l/second via a face mask. Following application of EER, mean FRC increased by 40.8% (P less than 0.05). The work of breathing was significantly increased after the EER was applied; there was also a significant increase in measured expiratory resistance and a decrease in inspiratory-expiratory time ratio. The change in lung volume was rapid, requiring less than five seconds for the new end-expiratory level to be reached. Dynamic lung compliance, inspiratory resistance, and respiratory rate did not change during any phase of the study. The application of external expiratory resistance may have potential therapeutic value by increasing lung volume in infants recovering from respiratory disease.

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Fourteen intubated infants recovering from neonatal respiratory disease had arterial blood gases and lung mechanics measured in the supine position and in two variants of the prone position. Prone positioning resulted in significant increases in mean (+/- SEM) arterial oxygen tension (Pa(o2 70.4 +/- 2.5 to 81.1 +/- 4.4mm Hg), dynamic lung compliance (1.7 +/- 0.24 to 2.55 +/- 0.37 ml/cm H2O),and tidal volume (8.6 +/- 1.0 to 10.5 +/- 1.2 ml) when all prone values were compared to supine values. Prone positioning with the abdomen protruding freely, when compared to all supine values, was associated with significantly increased dynamic lung compliance and tidal volume. Values for prone-abdomen free were not significantly different from values for prone-abdomen restricted. This suggests that there are clinical benefits from prone positioning in neonates recovering from respiratory disease.

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To investigate physiologic alterations in respiratory function associated with chest physiotherapy, arterial blood gases, respiratory patterns, lung mechanics, and functional residual capacity were measured in 13 neonates (weights 1.25 to 3.20 kg) during the control period, after vibration of the chest and suctioning, after hyperventilation, and two hours after suctioning. Compared to control values, mean PO2decreased significantly after suctioning to 43 mm Hg and increased significantly after hyperventilation to 78 mm Hg. There was a significant decrease in inspiratory resistance and a trend toward decrease in expiratory resistance after suctioning, with return to control levels after hyperventilation. Respiratory rate increased significantly after suctioning. Functional residual capacity, dynamic lung compliance, and tidal volume, as well as PCO2 and base excess, were not changed appreciably throughout the protocol. Because of potentially severe hypoxemia, this study suggests that suctioning and hyperventilation are not warranted on a routine basis in infants recovering from respiratory diseases.

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