Nancy E. Kechner

Physiologic, Biochemical, and Histologic Correlates Associated with Tidal Liquid Ventilation

Tidal liquid ventilation (TLV) with perfluorochemical fluid (PFC) has been successfully used experimentally for up to 4 h. However, no studies of prolonged TLV have been reported. We hypothesized that full-term newborn lambs can safely and effectively be liquid-ventilated for up to 24 h. To test this hypothesis, 17 lambs were liquid-ventilated; 7 for 4 h, 5 for 12 h, and 5 for 24 h. Arterial blood samples were obtained for PFC uptake, lipid analysis, and blood gas measurements. Tissues were obtained for histologic and biochemical analysis. Arterial blood gas and mean arterial blood pressure were as follows(mean ± SEM): pH 7.48 ± 0.04; PaCO2 30.6 ± 2.8; PaO2 424 ± 17; mean arterial pressure 76 ± 16 mm Hg. PFC blood levels increased rapidly to a mean of 5.2 ± 3.9 μg/mL. PFC tissue levels increased significantly (p < 0.01) from 260± 45 μg/g at 4 h to 400 ± 140 μg/g at 12 h. There was no further increase in PFC tissue levels by 24 h (456 ± 181 μg/g). There was a significant difference in PFC concentration as a function of tissue (p < 0.01). Furthermore, there was a significant correlation (r = 0.88; p < 0.01) between the amount of PFC and lipid in blood and tissue. Microscopic examination of the lungs demonstrated no evidence of barotrauma. These data demonstrate that prolonged TLV can be safe and efficacious for up to 24 h in full-term newborn lambs.

Comparison of natural surfactant and brief liquid ventilation rescue treatment in very immature lambs : Clinical and physiological correlates

We studied the effect of rescue therapy with modified porcine surfactant (Curosurf) or brief perfluorocarbon liquid ventilation on pulmonary gas exchange, mechanics and structure in very immature lambs. Both rescue strategies produced an improvement in arterial oxygenation and were able to support CO2 elimination. Histology showed unevenly inflated lungs in all but tidal-liquid-ventilated lambs. We speculate that due to immature lung architecture and relatively high permeability, previous exposure to gas ventilation impeded full effectiveness of both rescue modalities, perhaps prophylactic surfactant or liquid ventilation could be a better alternative.

Influences on Perfluorochemical (PFC) Blood Uptake: In-Vitro Assessment. ♦ 322

Intratracheal instillation of PFC liquid has been shown to improve pulmonary mechanics and support gas exchange in animals and humans with respiratory insufficiency. During this process, PFC is detected in the blood; the effect of physicochemical properties of PFC liquids and physiologic factors on uptake have not been quantitated previously. The purpose of this study was to evaluate the relative influence of physiochemical (PFC vapor pressure - VP, relative lipid solubility - PFC lipid α) and physiologic(surface area - SA, blood flow - Q, blood lipid content - L) factors on the rate and magnitude of blood PFC uptake. A closed system, temperature and flow controlled, recirculating table top circuit was designed; PFC liquids (LiquiVent®, APF 140M, or RIMAR 101) were circulated countercurrent to sheep blood through membranes (Sci-Med™) in separate experiments. APF 140M was compared to Rimar 101 and LiquiVent® to assess the effect of PFC VP (mmHg) and PFC lipid α, respectively. The effect of SA (M2) was assessed by comparing LiquiVent® uptake across two membranes. Q (ml/min) was changed and Intralipid™ was added to blood to assess the effect of Q and L (mg/gm), respectively, on LiquiVent® blood uptake. Serially sampled blood was analyzed by electron capture gas chromatography to measure blood PFC content (μgm PFC/gm blood). Peak PFC content (Cpeak) and the time constant (τ. min) associated with time to equilibration were analyzed to evaluate magnitude and rate of PFC uptake (*p< 0.01).

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

Antioxidant Enzyme (AOE) Activities in Liquid Ventilated Premature Lambs.|[dagger]| 1500

Total liquid ventilation (TLV) has been established as a ventilatory strategy for experimental respiratory distress that minimizes lung barotrauma and markedly improves physiologic outcome. The biochemical mechanisms that underlie these improvements are not understood. To evaluate the effect of age and ventilation strategy on pulmonary AOE activity, four groups of premature lambs [n = 27] (110 ± 3 days and 120 ± 2 days gestation) were supported for 4 hrs with either gas ventilation (GV) or TLV with LiquiVent® (FIO2 = 1.0). AOE activity of superoxide dismutase (tSOD), glutathione peroxidase (GPX), and catalase were normalized to tissue protein and compared to their age-matched fetal controls. Histological analysis was performed. (X ± SE; units/ mg protein).Table

DEVELOPMENTAL DIFFERENCES IN PERFLUBRON UPTAKE INTO THE BLOOD DURING TIDAL LIQUID VENTILATION (TLV) IN THE IMMATURE LAMB. |[dagger]| 1310

Tidal liquid ventilation (TLV) with perfluorochemical liquids (PFC) has been shown to provide effective gas exchange in term and preterm lambs with respiratory failure. PFCs have very low surface tensions and have high respiratory gas solubilities. It is these physical characteristics that make PFC an ideal media with which to support gas exchange in the stiff, noncompliant lungs characteristic of Infant Respiratory Distress Syndrome(IRDS). Although PFC is bioinert, nontoxic, and nonbiotransformable, a small quantity does cross into the blood. To determine if there is a developmental difference in PFC uptake in an animal model which resembles the cardiopulmonary development of human neonates currently receiving PFC therapy, 2 groups of premature lambs [Gr 1: 111 ±.23 days; n=6) and Gr 2: 123±.95 days; n=6)] were delivered by caesarean section, anesthetized, paralyzed, tracheotomized, placed on a time-cycled, pressure-limited tidal liquid ventilator, and ventilated with perflubron (Liquivent®: Alliance Pharm. Corp.) for 4 hours. Ventilation was modulated to maintain physiologic blood gases. Blood PFC content was determined by headspace analysis using an electron capture detector gas chromatograph on samples taken in utero, every 15 mins up to 1 hour, and every 30 mins to 4 hrs. These data were compared to that of previously evaluated term lambs (Pediatr Res (37): A1414). Results in μgm/gm (mean ± SE) are presented below:Table These data demonstrate that very minute (all values < 10μgm/gm) but different (*p<.01) quantities cross into the blood of the immature lamb following tidal liquid ventilation. The mean over 4 hrs for Gr 1, Gr 2, and the term lambs were 4.31 ±.29, 6.97±.36, and 7.35 ±.36, respectively, showing comparable levels in term and preterm blood perflubron content. These data suggest that even in the presence of high lung permeability of prematurity, perflubron blood content does not exceed that of a normal, term newborn lamb.(Supp by AlliancePharm Corp,R29HD26341)

PERFLUOROCHEMICAL (PFC) BLOOD UPTAKE DURING PARTIAL LIQUID VENTILATION: EFFECT OF LUNG CONDITION. † 1998

PERFLUOROCHEMICAL (PFC) BLOOD UPTAKE DURING PARTIAL LIQUID VENTILATION: EFFECT OF LUNG CONDITION. † 1998