Thomas F. Miller

Liquid assisted ventilation: An alternative ventilatory strategy for acute meconium aspiration injury

Evidence of surfactant inactivation by meconium has led to the use of exogenous surfactant therapy in the management of meconium aspiration syndrome (MAS). Liquid assisted ventilation has been shown to improve the cardiopulmonary function in lungs with high surface tension. We compared exogenous surfactant therapy with liquid assisted ventilation in the management of experimental acute meconium aspiration injury. Thirty‐two newborn lambs were ventilated at peak inspiratory pressures of 13–16 cm H2O, positive end expiratory pressure of 3–4 cm H2O, fractional inspired oxygen concentration (F1O2) of 1.0, and a respiratory frequency range between 30 and 35 breaths/min. Baseline arterial blood gases, pulmonary function, and arterial blood pressure measurements were taken. All lambs were given 2–3 ml/kg of an unfiltered 25% meconium solution. Lambs were then randomized into either gas‐ventilated meconium control, or one of three treatment groups: 1) surfactant; 2) partial liquid ventilation (PLV); or 3) total liquid ventilation (TLV) for 4 hours after meconium injury. All treated groups demonstrated a significant increase in arterial oxygenation (P < 0.05); surfactant and PLV‐treated lambs demonstrated significantly decreased arterial PCO2 (P < 0.05). Compliance in all groups increased compared with injury values; compliance of the TLV group increased more than in all other treatment groups (P < 0.05). In addition, lung histology of the TLV group demonstrated clear, intact alveolar epithelium and homogeneously expanded alveoli, while no such improvement was evident in the other groups. These data suggest roles for both exogenous surfactant therapy and liquid assisted ventilation techniques in the management of MAS. Pediatr Pulmonol. 1996; 21:316–322.

Effects of partial liquid ventilation with perfluorodecalin in the juvenile rabbit lung after saline injury.

Objective: To evaluate the feasibility of using the perfluorochemical, perfluorodecalin, for partial liquid ventilation (PLV) with respect to gas exchange and lung mechanics in normal and saline‐injured lungs of juvenile rabbits. Design: Experimental, prospective, randomized, controlled study. Setting: Physiology laboratory at a university medical school. Subjects: Seventeen juvenile rabbits assigned to three groups. Interventions: The conventional mechanical ventilation (CMV)‐injury group (n = 5) was treated with CMV after establishing a lung injury; the PLV‐injury group (n = 6) was treated with PLV after lung injury; and the PLV‐healthy group (n = 6) was supported with PLV without lung injury. Lung injury was created by repeated saline lung lavages. PLV‐treated animals received a single dose of intratracheal perfluorodecalin at a volume equal to the measured preinjury gas functional residual capacity (functional residual capacity = 18.6 ± 1.5 [SEM] mL/kg). Measurements and Main Results: Sequential measurements of total respiratory compliance and arterial blood chemistries were performed in all groups. Oxygenation index (OI) and ventilation efficiency index were calculated. After lung injury, there was a significant (p < .05) decrease in PaO2, total respiratory compliance, and ventilation efficiency index and an increase in OI and PaCO2. In the PLV‐injury group, PLV significantly (p < .05) improved PaO2 (+60%) and OI (−33%) over time. Compliance was significantly (p < .05) higher (90%) than in the CMV‐injury group over time. Conclusions: These results demonstrate that PLV with perfluorodecalin improved oxygenation and increased respiratory compliance in the saline‐injured rabbit lung. In addition, similar to the effects of several other perfluorochemical liquids on normal lungs, pulmonary administration of perfluorodecalin was associated with a small impairment in gas exchange and a significant decrease in lung compliance in the juvenile rabbit model.

Quantitative structure-activity relationships of perfluorinated hetero-hydrocarbons as potential respiratory media : Application to oxygen solubility, partition coefficient, viscosity, vapor pressure, and density

&NA; It has been extensively reported that liquid‐assisted ventilation, using inert perfluorocarbon liquids (PFCs), can reduce interfacial surface tension and allow for improved ventilation at decreased alveolar pressures. PFCs are bioinert, minimally absorbed, and have no deleterious histologic, cellular, or biochemical effects when used as respiratory media. Although several types of PFCs have been characterized, a select few are considered to be compatible with life. Compatibility is often related to the physicochemical profile inherent to the PFC liquids. It is essential that certain physical properties such as respiratory gas solubility, vapor pressure, density, viscosity, and tissue permeability be within a narrow, acceptable range for a PFC to be considered as a possible candidate for respiratory media. The current study sought to characterize the physicochemical profile of commercially available PFCs. This was accomplished by creating a method for accurate, rapid prediction of a host of unknown physical characteristics of PFCs. The physicochemical properties of 16 perfluorinated hetero‐hydrocarbons were catalogued from the literature. The input data were categorized into three major groups: empiric properties, geometric indices, and quantum mechanical descriptors, to generate a database. Algorithms were then developed, one for each dependent variable (FUNCTION), including oxygen solubility, partition coefficient (logP), vapor pressure, viscosity, and density, that related the values of these physical properties of potential breathable PFC liquids to the parameters listed in the database. The general form of the algorithm can be written as follows: FUNCTION = &Sgr;(CiPi/|Pi|) + constant; where the FUNCTIONS are oxygen solubility, logP, vapor pressure, viscosity, and density. Ci is a coefficient that weights the relative contribution of each parameter. Each independent parameter, Pi, was normalized by the average value of the parameter used in the analysis, |Pi|. Residual analysis demonstrated validity with all five equations. This method is expected to assist in the prediction of physical properties of PFC liquids with acceptable accuracy, such that PFC production and selection from currently available liquids can be optimized for each liquid ventilation application. ASAIO Journal 1996;42:968‐973.

Effect of single versus multiple dosing on perfluorochemical distribution and elimination during partial liquid ventilation

The objective of this study was to quantitate perfluorochemical (PFC) elimination kinetics during partial liquid ventilation (PLV) following an initial fill with or without hourly dosing. Young New Zealand rabbits were studied in two groups: Gr I (n = 6), PLV with a single dose of PFC liquid (perflubron: LiquiVent®, Alliance Pharmaceutical Corp.); and Gr II (n = 5), PLV with PFC liquid and multiple hourly dosing . All rabbits were studied for 4 h, following initial instillation of a volume of PFC liquid equal to the measured gas functional residual capacity. Animals were ventilated at a constant breathing frequency (30 br/min), tidal volume (9.3 ± 0.3 SE mL/kg), positive end expiratory pressure (4 cm H2O), and inspiratory time (0.30 s). PFC saturation of mixed expired gas (PFC‐Sat) was assessed with a thermal conductivity analyzer, and PFC elimination was calculated from PFC‐Sat, minute ventilation, and temperature of the expired gas. In GR II, PFC was supplemented hourly at a volume determined by PFC elimination calculations.

Virtual bronchoscopy with perfluoronated hydrocarbon enhancement

RATIONALE AND OBJECTIVES Bronchoscopic computed tomography (CT) is limited by machine resolution and air-soft-tissue contrast. The objective of this study was to determine whether improving the contrast by using the contrast agent perflubron (PFOB) in the lung would improve the bronchoscopic CT technique and permit visualization of small airways. MATERIALS AND METHODS Bronchoscopic CT was performed in an anesthetized 8-week-old New Zealand white rabbit before and after the endotracheal administration of PFOB. RESULTS Bronchoscopic CT performed with PFOB permitted navigation of bronchi as small as 0.8 mm in diameter, which are much smaller than those that can be navigated without PFOB. CONCLUSION In this example, the use of perfluorochemicals with bronchoscopic CT enhanced the capabilities of virtual bronchoscopy.

EFFECTS OF PARTIAL LIQUID VENTILATION (PLV) WITH PERFLUORODECALIN IN THE SALINE INJURED LUNG OF THE JUVENILE RABBIT MODEL. † 2286

Several perfluorochemical (PFC) liquids with different and specific physical properties have been used as a means of improving pulmonary gas exchange and lung mechanics during respiratory distress. We evaluated APF-140M(Air Product and Chemicals, Inc.) with respect to gas exchange and lung mechanics in healthy and saline injured(SI) lungs of the juvenile New Zealand White rabbit. SI was created by repeated lung lavages (4-16 times, 10 cc/kg/lavage) with warm saline solution. PLV treated animals received intratracheal APF-140M at a volume equal to the measured pre-injury gas functional residual capacity (FRC = 18.6 ± 1.5 ml/kg). Seventeen rabbits, (age: 7-9 wks; wt. = 1.59 ± 0.1 kg SE) were assigned to three groups. Gr I (n=5) was treated with conventional mechanical ventilation (CMV) after establishing SI, Gr II (n=6) was treated with PLV after SI. Gr III (n=6) was supported with PLV without injury. All rabbits were supported with CMV gas ventilator strategy in which frequency was maintained constant and ventilatory pressures were adjusted to maintain constant tidal volume and minute ventilation. Sequential measurements of dynamic compliance(C) and arterial blood chemistry were performed in all groups (ie. after instrumentation, injury) and hourly for 4 hours thereafter. Oxygenation index (OI), and ventilation efficiency index(VEI) were calculated. Mean±SEM data at baseline(BI), Injury (Inj), 1 hour (1H), and 4 hours(4H) were:Table These data demonstrate: 1) following lung injury there was a significant (p<0.05) decrease in PaO2, C, VEI and increase in OI. 2) In Gr II, PLV significantly (p<0.05) improved PaO2 and OI. C was significantly (p<0.05) higher than Gr I at 1H. 3) there was a significant (p<0.05) decrease in C following PLV in Gr III. These results indicate that PLV with APF-140M caused a transient improvement in oxygenation and lung mechanics in the saline injured lung and sustained impairment of C in healthy lung of the juvenile rabbit model.(Supp in part by R29HD26341)

COMBINED ECMO AND PARTIAL LIQUID VENTILATION (PLV) IN HUMAN NEONATES: LIQUIVENT® PERFLUOROCHEMICAL (PFC) ELIMINATION. † 1368

COMBINED ECMO AND PARTIAL LIQUID VENTILATION (PLV) IN HUMAN NEONATES: LIQUIVENT® PERFLUOROCHEMICAL (PFC) ELIMINATION. † 1368

Prolonged Total Liquid Ventilation in Premature Lambs. ♦ 1064

Liquid ventilation with continuous tidal movement of oxygenated perfluorochemical (PFC) liquid (total liquid ventilation: TLV) has been shown to improve lung mechanics and provide effective gas exchange in animal models with respiratory failure. We hypothesize that premature lambs can be safely and adequately ventilated for a prolonged period of time with TLV. To test this hypothesis, we evaluated the physiological, histological, and biochemical profile in 9 preterm lambs (132 day gestation; 2.7-4.7 kg) who were supported up to 72 hours with a time-cycled, pressure-limited liquid ventilator (PFC: LiquiVent®Alliance Pharm. Corp. Temp. = 36°C, FiO2 = 0.48-1.0, rate = 4/min, I:E = 1:3, TV = 19-26 ml/kg). Lambs were anesthetized and instrumented with tracheal. carotid, and venous cannulae. Arterial blood samples were obtained for PFC uptake and blood gas measurements. PFC analysis was done by electron capture and flame ionization gas chromatography and expressed in mcg of PFC/gm of blood or PFC gm/tissue. Compliance was calculated using stop-flow alveolar pressure determinations. Tissues were obtained for histologic and biochemical analysis. Animals were time killed at 4, 24, and 72 hours. By 15 min of TLV, PFC levels were 5.1 ± 0.93 and stayed within an average of 7.5 ± 0.30 over 24 hours. The gas exchange and cardiovascular profiles (harmonic mean ± SE) were; pH = 7.34± 0.004, pCO2 =44.3±0.45, pO2 = 177 ± 5.8, compliance = 1.75± 0.04 ml/cmH2O/kg, mean blood pressure = 51± 0.62, heart rate = 189 ± 1.78. Histology demonstrated well-expanded gas exchange spaces without evidence of edema, exudate, or cellular debris. Tissue and blood biochemical analyses are ongoing. These data demonstrate that prolonged TLV can support gas exchange, and provide cardiovascular stability for up to 72 hours with minimal accumulation of PFC in blood in premature lambs.

BIOCHEMICAL AND HISTOLOGIC INDICES OF REDUCED PULMONARY TRAUMA DURING PERFLUOROCHEMICAL (PFC) LIQUID VENTILATION |[dagger]| 2119

Urinary excretion of desmosine (DES), an index of proteolytic destruction of lung elastin, has been shown to be greater in premature infants who ultimately developed bronchopulmonary dysplasia (ARRD 131:568, 1985). Tidal liquid ventilation (TLV) in immature animals has been shown to improve pulmonary gas exchange at lower ventilatory pressures while preserving lung architecture as compared to conventional gas ventilation (CMV) (J Appl Physiol 72:1024, 1992). These improvements have been related to removal of the gas-liquid interface, reduction of interfacial alveolar surface tension, improved pulmonary compliance and lung volume recruitment. Larger tidal volumes (VT) and lower breathing frequencies are used during TLV as compared to CMV to minimize resistive pressures and diffusional factors. To compare these two forms of ventilation with respect to biochemical and histologic indices of lung trauma, 17 immature lambs (117 ± 1.4 SE dys gest.) were delivered by cesarean section and supported with CMV (n = 6) or TLV with PFC liquid (LiquiVent)(n = 11) for 4 hrs. Arterial blood chemistry and lung mechanics were serially assessed; urine was continually collected and assayed for DES as an index of elastin turnover. Lung samples were prepared for light microscopy and morphometric analysis including area of gas exchange spaces (GES). Data is expressed as mean ± SE over the 4 hr protocol (*p < 0.05). In addition, there was an increase in DESM over time in both groups which was less in the TLV (+25%) as compared to GV (+49%) animals. TLV lungs were intact and expanded homogeneously and GV lungs demonstrated patchy expansion and disruption of alveolar-capillary membranes across all regions. These data demonstrate that TLV supports improved oxygenation and distribution of ventilation at lower ventilatory pressures with greater gas exchange area and reduced elastin turnover as compared to GV. The results indicate that TLV minimizes pulmonary trauma associated with positive pressure ventilation. As such, this study suggests that TLV provides a gentle form of ventilatory support which has the potential to foster lung development and reduce the risk of chronic pulmonary sequelae in the immature infant. (Supp by NIH R29HD26341; Alliance Pharmaceutical Corp.)Table

The Longitudinal Course of Perfluorochemical (PFC) Intrapulmonary Distribution, Uptake, and Elimination in a Chronic Rabbit Model. † 1547

The Longitudinal Course of Perfluorochemical (PFC) Intrapulmonary Distribution, Uptake, and Elimination in a Chronic Rabbit Model. † 1547