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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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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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Pulmonary function tests were performed on 36 very low birth weight neonates (birth weight less than or equal to 1000 gm, gestational age less than or equal to 30 weeks, appropriate size for gestational age) from birth until 8 weeks of age. Tidal airflow was measured by means of a pneumotachygraph, and the transpulmonary pressure changes were determined by the esophageal balloon technique. Pulmonary mechanics and energetics were calculated by the least mean square analysis technique at 1/2, 1, 2, 4, 6, and 8 weeks of age. Compliance was lowest at 2 weeks and subsequently increased linearly (at approximately 0.1 ml/cm H2O/wk). When compliance was based on body weight, however, no change was noted with advancing age. Resistance was greatest at 2 weeks and subsequently decreased. The infants maintained a normal minute ventilation with a slightly increased resistive work of breathing. Despite our ability to wean 53% of the infants to room air by 8 weeks, none of them had pulmonary mechanics considered normal for term infants. Infants with and without bronchopulmonary dysplasia (BPD) had similar patterns of pulmonary development. At 8 weeks of age, the pulmonary mechanics in infants with BPD who had been weaned to room air were comparable to those in infants without BPD, an observation that calls into question the rationale for defining BPD at 4 weeks in this population. These data suggest that such pulmonary function profiles provide evidence of persistent lung parenchymal abnormalities.

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