Cynthia Cox

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.

Nasal cannula, CPAP, and high-flow nasal cannula: effect of flow on temperature, humidity, pressure, and resistance.

BACKGROUND Delivery of warm, humidified, supplemental oxygen via high-flow nasal cannula has several potential benefits; however, the high-flow range may not maintain humidification and temperature and in some cases may cause excessive expiratory pressure loading. OBJECTIVE To compare the effect of flow on temperature, humidity, pressure, and resistance in nasal cannula (NC), continuous positive airway pressure (CPAP), and high-flow nasal cannula (HFNC) in a clinical setting. METHODS The three delivery systems were tested in the nursery using each instruments recommended specifications and flow ranges (0-3 L/min and 0-8 L/min). Flow, pressure, temperature, and humidity were measured, and resistance was calculated. RESULTS For all devices at 0-3 L/min, there was a difference (p<0.01) in temperature (NC 35.9°C > CPAP 34.5°C > HFNC 34.0°C), humidity (HFNC 82% > CPAP 77% > NC 57%), pressure (HFNC 22 cmH(2)O > NC 4 cmH(2)O > CPAP 3 cmH(2)O), and resistance (HFNC 636 cmH(2)O/L/sec > NC 270 cmH(2)O/L/sec > CPAP 93 cmH(2)O/L/sec) as a function of flow. For HFNC and CPAP at 0-8 L/min, there was a difference (p<0.01) in temperature (CPAP 34.5°C > HFNC 34.0°C) in humidity (HFNC 83 % > CPAP 76 %), pressure (HFNC 56 cmH(2)O > CPAP 14 cmH(2)O) and resistance (HFNC 783 cmH(2)O/L/sec > CPAP 280 cmH(2)O/L/sec) as a function of flow. CONCLUSIONS Gas delivered by HFNC was more humid than NC and CPAP. However, the higher pressure and resistance delivered by the HFNC system may have clinical relevance, such as increased work of breathing, and warrants further in vivo studies.

Liquid ventilation: Gas exchange, perfluorochemical uptake, and biodistribution in an acute lung injury.

Objective Compare the physiologic, histologic, and biochemical findings of tidal and partial liquid ventilation (PLV) with gas ventilated lambs with an acute lung injury. Design Experimental, prospective randomized controlled study. Setting School of medicine, department of physiology. Subjects Eighteen newborn lambs (≤1 wk old). Interventions Injury was established by using HCl saline lavages. Seven lambs underwent tidal liquid ventilation (TLV), five underwent PLV, and six underwent gas ventilation (GV) for 4 hrs. Measurements Sequential arterial blood chemistries were performed. Ventilation efficiency index, arterial-alveolar Po2, and physiologic shunt were calculated. Blood and tissue were analyzed for perfluorochemical fluid. Histologic examinations of lungs were performed. Main Results TLV oxygenation was significantly better (p < .001) than PLV and GV. Paco2 was similar in all three groups. Ventilation efficiency index was significantly better (p < .01) in the TLV group as compared with the PLV and GV groups. Physiologic shunt was significantly less in the TLV injury group (p < .01) than the PLV and GV groups. Perfluorochemical fluid blood level of 2.3 ± 0.32 &mgr;g/mL in the PLV group was significantly lower (p < .01) than TLV of 7.8 ± 0.71 &mgr;g/mL; there was a difference (p < .01) as function of time in the TLV and no difference in the PLV injury group. There were no differences in tissue perfluorochemical fluid levels as a function of ventilation ([mean ± sem] TLV, 219 ± 26 &mgr;g/g; PLV injury, 184 ± 26 &mgr;g/g). There was a significant difference in perfluorochemical fluid levels as a function of tissue (p < .001). Conclusion In severe lung injury, this study demonstrates that physiologic gas exchange can be maintained with TLV or PLV. Physiologic shunt was less in the TLV group as compared with PLV or GV. Additionally, perfluorochemical fluid in the blood and tissue is low during PLV and TLV relative to that associated with intravenous administration of perfluorochemical fluid emulsion.

Long-Term Tidal Liquid Ventilation in Premature Lambs: Physiologic, Biochemical and Histological Correlates

Chronic lung disease in infants continues to be problematic. Tidal liquid ventilation (TLV) improves lung mechanics and provides effective gas exchange. We hypothesized that premature lambs could be supported safely with TLV and evaluated 9 preterm lambs (132 days gestation) on TLV up to 72 h. Results (mean ± SEM): pH 7.36 ± 0.003, PaCO2 44 ± 0.34 mm Hg, PaO2 170 ± 4.8 mm Hg, compliance = 1.65 ± 0.24 ml/cm H2O/kg, mean arterial blood pressure = 53 ± 0.08 mm Hg, heart rate = 189 ± 1.5 bpm. Blood perflubron levels were 6.0 ± 0.24 µg/ml over 24 h. Tissue perflubron levels increased from 81 ± 7.0 µg/g at 24 h to 108 ± 15 µg/g at 72 h (p < 0.05). There was a difference in perflubron concentrations as a function of tissue (p < 0.001) that correlated to lipid levels (r2 = 0.93, p < 0.01). These data demonstrate that TLV is both safe and effective up to 72 h in premature lambs.

Comparison of perfluorochemical fluids used for liquid ventilation: Effect of endotracheal tube flow resistance

Neonatal endotracheal tubes with small inner diameters are associated with increased resistance regardless of the medium used for assisted ventilation. During liquid ventilation (LV) reduced interfacial tension and pressure drop along the airways result in lower alveolar inflation pressure compared with gas ventilation (GV). This is possible by optimizing liquid ventilation strategies to overcome the resistive forces associated with liquid density (ρ) and viscosity (μ) of these fluids. Knowledge of the effect of ρ, μ, and endotracheal tube (ETT) size on resistance is essential to optimize LV strategies. To evaluate these physical properties, three perfluorochemical (PFC) fluids with a range of kinematic viscosities (FC‐75 = 0.82, LiquiVent™ = 1.10, APF‐140 = 2.90) and four different neonatal ETT tubes (Mallincrokdt Hi‐Lo Jet™ ID 2.5, 3.0, 3.5, and 4.0 mm) were studied. Under steady‐state flow, flow and pressure drop across the ETTs were measured simultaneously. Resistance was calculated by dividing pressure drop by flow, and both pressure‐flow and resistance‐flow relationships were plotted. Also, pressure drop and resistance were each plotted as a function of kinematic viscosity at flows of 0.01 L · s−1 for all four ETT sizes.

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

SELECTIVE PULMONARY VASODILATION AND PULMONARY DISTRIBUTION OF RADIOLABELED HISTAMINE DURING LIQUID VENTILATION (LV) IN HYPOXIC NEWBORN (NB) LAMBS|[dagger]| 2336

Histamine (H) is a selective pulmonary vasodilator in the fetus and NB. During total LV (TLV), significant decreases in pulmonary artery pressure(Ppa) without systemic effects have been reported during hypoxia-induced pulmonary hypertension following intravenous (IV) and pulmonary administration of drug (PAD) delivering equal doses of H, however during partial liquid ventilation (PLV) there were no PAD effects. To test the hypothesis that differences in the homogeneity of drug distribution within the lung contribute to the differences in PAD effects of H during PLV compared to TLV, we compared both the pulmonary and systemic vascular effects and the pulmonary distribution of H following PAD delivery of 0.05 μg/kg as 0.5cc/kg bolus at the beginning of inspiration during PLV and TLV. NB lambs (n=14) were studied(2.5-5.0 kg) during hypoxia (PaO2:20-35 mm Hg) during both PLV and TLV, using a perfluorochemical (PFC) (LiquiVent®). Ppa and systemic arterial pressure (SAP) were continuously monitored; physiologic pH and normocarbia were maintained. Radiolabeled (3H) histamine was delivered to randomly selected animals in a supine position using PAD delivery during TLV and PLV. Lungs were hung and dried with continuous distending pressure of 30 cm H2O and sectioned using a standardized matrix method; samples were weighed, digested and radioactivity counted. Pulmonary distribution was assessed by normalizing the radioactivity of each piece (per dry weight) to the average radioactivity of all pieces in ratio form (uniform distribution resulting in a value of one for each piece) and all ratios were expressed in histogram form. During TLV, PAD H decreased Ppa significantly (p<0.02) and SAP did not change. During PLV, PAD H did not change Ppa or SAP. Representative distribution data using PAD during TLV resulted in 48% of pieces having ratio values between 0.8-1.2. Using PAD during PLV resulted in 14% of samples having ratio values between 0.8-1.2. We conclude that PAD delivery of H during TLV is an effective way of achieving pulmonary selective decreases in vascular pressure, due in part to more homogeneous distribution within the lung. We speculate that alternative techniques for drug delivery with liquid ventilation, such as creating a suitable emulsion of drug in PFC liquid for delivery with the initial fill of the lung, may allow improved pulmonary distribution of drug during both PLV and TLV. (Supp in part by Alliance Pharm Comp and Wyeth Pharm)

Tidal Liquid Ventilation (TLV) Transition to Spontaneous Breathing(SB): 24 Hour Follow-up of Physiologic and Radiographic Correlates 1748

Tidal Liquid Ventilation (TLV) Transition to Spontaneous Breathing(SB): 24 Hour Follow-up of Physiologic and Radiographic Correlates 1748