Liquid ventilation attenuates pulmonary oxidative damage.

PURPOSE: Liquid perfluorochemicals reduce the production of reaction oxygen species by alveolar macrophages. We sought to determine whether the use of liquid perfluorochemicals in vivo during liquid ventilation would attenuate oxidative damage to the lung. MATERIALS AND METHODS: Healthy infant piglets (n = 16) were instrumented for mechanical ventilation and received intravenous oleic acid to create an acute lung injury. The animals were assigned to a nontreatment group receiving conventional mechanical ventilation or a treatment group receiving partial liquid ventilation with a liquid perfluorochemical. Following sacrifice, the bronchoalveolar lavage and lung parenchyma were analyzed for evidence of oxidative damage to lipids and proteins by determination of TBARS and carbonylated protein residues, respectively. RESULTS: Mortality in the control group was 50% at the completion of the study compared with no deaths in the partial liquid ventilation group (P = .025). The alveolar-arterial oxygen difference was more favorable following injury in the partial liquid ventilation group. The liquid ventilation group demonstrated a 32% reduction in TBARS (P = .043) and a 14% reduction in carbonylated protein residues (P = .061). CONCLUSION: These data suggest that partial liquid ventilation supports gas exchange and reduces mortality in association with a reduction in the production of reactive oxygen species and the concomitant attenuation of tissue damage during the early phase of acute lung injury.

Regional pulmonary blood flow during partial liquid ventilation in normal and acute oleic acid-induced lung-injured piglets.

OBJECTIVE: To determine the spatial distribution of pulmonary blood flow in three groups of piglets: partial liquid ventilation in normal piglets, partial liquid ventilation during acute lung injury, and conventional gas ventilation during acute lung injury. DESIGN: Prospective randomized study. SETTING: A university medical school laboratory approved for animal research. SUBJECTS: Neonatal piglets. INTERVENTIONS: Regional pulmonary blood flow was studied in 21 piglets in the supine position randomized to three different groups: a normal group that received partial liquid ventilation (Normal-PLV) and two acute lung injury groups that received an oleic acid-induced lung injury: partial liquid ventilation during acute lung injury (OA-PLV) and conventional gas ventilation during acute lung injury (OA-Control). Acute lung injury was induced by infusing oleic acid (0.15 mL/kg iv) over 30 mins. Partial liquid ventilation was instituted with perflubron (LiquiVent, 30 mL/kg) after 30 mins in the Normal-PLV and OA-PLV groups. MEASUREMENTS AND MAIN RESULTS: Arterial and venous blood gases, hemodynamics, and pulmonary mechanics were measured every 15 mins throughout the hour-long study. Pulmonary blood flow was assessed by fluorescent microsphere technique at baseline and after 30, 45, and 60 mins. In the Normal-PLV piglets, pulmonary blood flow decreased from baseline (before injury or partial liquid ventilation) in the most dependent areas of the lung (F ratio = 3.227; p < .001). In the OA-PLV piglets, pulmonary blood flow was preserved over time throughout the lung (F ratio = 1.079; p = .38). In the OA-Control piglets, pulmonary blood flow decreased in the most dependent areas of the lung and increased from baseline in less dependent slices over time (F ratio = 2.48; p = .003). CONCLUSIONS: The spatial distribution of regional pulmonary blood flow is preserved during partial liquid ventilation compared with gas ventilation in oleic acid-induced lung injury.

A report of the use of the Dynamic Objective Risk Assessment (DORA) score in the changing pediatric intensive care environment.

OBJECTIVE: To assess the clinical use of the Dynamic Objective Risk Assessment (DORA) severity of illness score in a site remote from its development. DESIGN: Prospective chart review. SETTING: Tertiary referral pediatric intensive care unit (PICU). PATIENTS: One hundred sixty consecutive admissions involving 621 patient days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pediatric Risk of Mortality (PRISM) scores were collected daily for all PICU patient days. Collection of data was performed by a physician not directly involved in the ordering of vital signs or laboratory data. The daily DORA score was calculated from the previous day's PRISM score and the admission PRISM score according to a previously described formula. The DORA score determines the patient's risk of mortality for the next 24 hrs. Also documented were the tests not ordered for each patient day. The sensitivity and specificity of the DORA score in our patient population were very similar to that previously reported using the previously described 1% cutoff for predicted mortality. We also noted that the tests ordered were related to the physician's perception of the patient's degree of sickness, and were themselves predictive of outcome. CONCLUSION: An outcome scoring system created in one group of PICUs can be applied to patients in another PICU remote from where the scoring system was developed with similar ability to predict outcome.

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange.

Partial liquid ventilation using conventional ventilatory schemes improves lung function in animal models of respiratory failure. We examined the feasibility of high-frequency partial liquid ventilation in the preterm lamb with respiratory distress syndrome and evaluated its effect on pulmonary and systemic hemodynamics. Seventeen lambs were studied in three groups: high-frequency gas ventilation (Gas group), high-frequency partial liquid ventilation (Liquid group), and high-frequency partial liquid ventilation with hypoxia-hypercarbia (Liquid-Hypoxia group). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over 5 h (arterial oxygen tension 253 +/- 21.3 vs. 17 +/- 1.8 Torr; P < 0.001). Pulmonary vascular resistance decreased 78% (P < 0.001), pulmonary blood flow increased fivefold (P < 0.001), and aortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia, hypercarbia, and shock in the Gas group. Central venous pressure did not change. The Liquid-Hypoxia group was similar to the Gas group. We conclude that high-frequency partial liquid ventilation improves gas exchange and stabilizes pulmonary and systemic hemodynamics compared with high-frequency gas ventilation. The stabilization appears to be due in large part to improvement in gas exchange.

Perfluorocarbon-associated gas exchange improves oxygenation, lung mechanics, and survival in a model of adult respiratory distress syndrome.

OBJECTIVE: To compare the effectiveness of perfluorocarbon-associated gas exchange to volume controlled positive pressure breathing in supporting gas exchange, lung mechanics, and survival in an acute lung injury model. DESIGN: A prospective, randomized study. SETTING: A university medical school laboratory approved for animal research. SUBJECTS: Neonatal piglets. INTERVENTIONS: Eighteen piglets were randomized to receive perfluorcarbon-associated gas exchange with perflubron (n=10) or volume controlled continuous positive pressure breathing (n=8) after acute lung injury was induced by oleic acid infusion (0.15 mL/kg iv). MEASUREMENTS AND MAIN RESULTS: Arterial and venous blood gases, hemodynamics, and lung mechanics were measured every 15 mins during a 3-hr study period. All animals developed a metabolic and a respiratory acidosis during the infusion of oleic acid. Following randomization, the volume controlled positive pressure breathing group developed a profound acidosis (p<.05), while pH did not change in the perfluorocarbon-associated gas exchange group. Within 15 mins of initiating perfluorocarbon-associated gas exchange, oxygenation increased from a PaO2 of 52 +/- 12 torr (6.92 +/- 1.60 kPa) to 151 +/- 93 torr (20.0 +/- 12.4 kPa) and continued to improve throughout the study (p<.05). Animals that received volume controlled positive pressure breathing remained hypoxic with no appreciable change in PaO2. Although both groups developed hypercarbia during oleic acid infusion, PaCO2, steadily increased over time in the control group (p<.01). Static lung compliance significantly increased postrandomization (60 mins) in the animals supported by perflurocarbon-associated gas exchange (p<.05), whereas it remained unchanged over time in the volume controlled positive pressure breathing group. However, survival was significantly higher in the perfluorocarbon-associated gas exchange group with eight (80%) of ten animals surviving the entire study period. Only two (25%) of the eight animals in the volume controlled positive pressure breathing group were alive at the end of the study period (log-rank statistic, p=.013). CONCLUSIONS: Perflurocarbon-associated gas exchange enhanced gas exchange, pulmonary mechanics, and survival in this model of acute lung injury.

Perfluorocarbon-associated gas exchange in normal and acid-injured large sheep.

OBJECTIVES: We hypothesized that a) perfluorocarbon-associated gas exchange could be accomplished in normal large sheep; b) the determinants of gas exchange would be similar during perfluorocarbon-associated gas exchange and conventional gas ventilation; c)in large animals with lung injury, perfluorocarbon-associated gas exchange could be used to enhance gas exchange without adverse effects on hemodynamics; and d) the large animal with lung injury could be supported with an FIO2 of <1.0 during perfluorocarbon-associated gas exchange. DESIGN: Prospective, observational animal study and prospective randomized, controlled animal study. SETTING: An animal laboratory in a university setting. SUBJECTS: Thirty adult ewes. MEASUREMENT AND MAIN RESULTS: Five normal ewes (61.0 +/- 4.0 kg) underwent perfluorocarbon-associated gas exchange to ascertain the effects of tidal volume, end-inspiratory pressure, and positive end-expiratory pressure (PEEP) on oxygenation. Respiratory rate, tidal volume, and minute ventilation were studied to determine their effects on CO2 clearance. Sheep, weighing 58.9 +/- 8.3 kg, had lung injury induced by instilling 2 mL/kg of 0.05 Normal hydrochloric acid into the trachea. Five minutes after injury, PEEP was increased to 10 cm H2O. Ten minutes after injury, sheep with Pao2 values of <100 torr (<13.3 kPa) were randomized to continue gas ventilation (control, n=9) or to institute perfluorocarbon-associated gas exchange (n=9) by instilling 1.6 L of unoxygenated perflubron into the trachea and resuming gas ventilation. Blood gas and hemodynamic measurements were obtained throughout the 4-hr study. Both tidal volume and end-inspiratory pressure influenced oxygenation in normal sheep during perfluorocarbon-associated gas exchange. Minute ventilation determined CO2 clearance during perfluorocarbon-associated gas exchange in normal sheep. After acid aspiration lung injury, perfluorocarbon-associated gas exchange increased PaO2 and reduced intrapulmonary shunt fraction. Hypoxia and intrapulmonary shunting were unabated after injury in control animals. Hemodynamics were not influenced by the institution of perfluorocarbon-associated gas exchange. CONCLUSIONS: Tidal volume and end-inspiratory pressure directly influence oxygenation during perfluorocarbon-associated gas exchange in large animals. Minute ventilation influences clearance of CO2. In adult sheep with acid aspiration lung injury, perfluorocarbon-associated gas exchange at an FIO2 of <1.0 supports oxygenation and improves intrapulmonary shunting, without adverse hemodynamic effects, when compared with conventional gas ventilation.

Prolonged studies of perfluorocarbon associated gas exchange and of the resumption of conventional mechanical ventilation.

OBJECTIVE: To determine whether oxygenation and lung mechanics are preserved during perfluorocarbon associated gas exchange of 24 hrs duration and after evaporation of perfluorocarbon. DESIGN: Prospective, experimental animal trials. SETTING: Animal laboratory in a university setting. SUBJECTS: Ten normal, neonatal piglets weighing 2.5 to 4.5 kg. INTERVENTIONS: Ten piglets were anesthetized with fentanyl (25 micrograms/kg/hr), paralyzed with metocurine iodide (0.3 mg/kg) and placed on volume regulated continuous positive pressure breathing instituted at an FIO2 setting of 1.0, tidal volume of 15 mL/kg, respiratory rate of 25 breaths/min and positive end-expiratory pressure of 4 cm H2O. Perfluorocarbon associated gas exchange was initiated by intratracheal instillation of perflouorooctylbromide (30 mL/kg) followed by gas ventilation at the same settings. Evaporative losses were replaced by intratracheal instillation of 2.5 mL/kg/hr of perfluorocarbon. In one group of five piglets, evaporative losses were replaced for 24 hrs until the end of the study. In the other group of five piglets, replacement of perfluorocarbon was discontinued after 2 hrs, although gas ventilation was continued for 24 hrs. Blood gases and lung mechanics were measured in both groups. Histologic evaluation of lungs from both groups of animals was performed. MEASUREMENTS AND MAIN RESULTS: Airway pressures and blood gases were stable throughout the 24-hr study period in both groups. Airway pressures in the evaporative group increased as evaporation of perfluorocarbon neared completion. There was no hemodynamic deterioration during the 24-hr study period. Histology showed good preservation of lung architecture in both groups. CONCLUSIONS: Perfluorocarbon associated gas exchange was safe and effective in normal piglets for a period of 24 hrs. Evaporation of perfluorocarbon and resumption of continuous positive pressure breathing was well tolerated.

Partial liquid ventilation in premature lambs with respiratory distress syndrome: efficacy and compatibility with exogenous surfactant.

OBJECTIVE: To determine the efficacy of partial liquid ventilation (PLV) by means of a medical-grade perfluorochemical liquid, perflubron (LiquiVent), in premature lambs with respiratory distress syndrome (RDS). Further, to determine the compatibility of perflubron with exogenous surfactant both in vitro and in vivo during PLV. DESIGN: Prospective, randomized, controlled study, with in vitro open comparison. SUBJECTS: Twenty-two premature lambs with RDS. INTERVENTIONS: In vitro assays were conducted on three exogenous surfactants before and after combination with perflubron. We studied four groups of lambs, which received one of the following treatment strategies: conventional mechanical ventilation (CMV); surfactant (Exosurf) plus CMV; PLV; or surfactant plus PLV. MEASUREMENTS AND MAIN RESULTS: In vitro surface tension, measured for three exogenous surfactants, was unchanged in each animal after exposure to perflubron. Lung mechanics and arterial blood gases were serially measured. All animals treated with PLV survived the 5 hours of experiment without complication; several animals treated with CMV died. During CMV, all animals had marked hypoxemia and hypercapnia. During PLV, arterial oxygen tension increased sixfold to sevenfold within minutes of initiation, and this increase was sustained; arterial carbon dioxide tension decreased to within the normal range. Compliance increased fourfold to fivefold during PLV compared with CMV. Tidal volumes were increased during PLV, with lower mean airway pressure. Resistance was similar for both CMV and PLV; there was no difference with surfactant treatment. CONCLUSIONS: We conclude that PLV with perflubron improves lung mechanics and gas exchange in premature lambs with RDS, that PLV is compatible with exogenous surfactant therapy, and that, as a treatment for RDS in this model, PLV is superior to the surfactant studied.

Cardiorespiratory effects of perfluorocarbon-associated gas exchange at reduced oxygen concentrations.

OBJECTIVE: To determine whether reducing FIO2 during perfluorocarbon-associated gas exchange would cause deterioration of hemodynamics, lung mechanics, or gas exchange in normal piglets. DESIGN: A prospective, controlled animal trial. SETTING: Experimental animal laboratory in a university setting. SUBJECTS: Twelve normal, anesthetized piglets, 7 to 14 days old, and weighing 3.31 +/- 0.75 kg. INTERVENTIONS: After the induction of anesthesia, tracheostomy and catheterization, piglets were stabilized. They were mechanically ventilated with a tidal volume of 15 mL/kg, inspiratory time of 25%, positive end-expiratory pressure of 4 cm H2O, and a respiratory rate of 20 to 28 breaths/min to obtain a baseline PaCO2 between 34 and 45 torr (4.7 and 6.0 kPa). Each animal was studied during continuous positive-pressure breathing, and during perfluorocarbon-associated gas exchange. They were ventilated at an FIO2 of 1.0 for 15 mins. FIO2 was randomly varied among 0.75, 0.5, and 0.3 every 15 mins, then returned to 1.0. At each FIO2, measurements of gas exchange, lung mechanics, and hemodynamics were made. After continuous positive-pressure breathing, perfluorocarbon-associated gas exchange was instituted by replacing the gaseous functional residual capacity of the lungs with perfluorooctylbromide. Animals were then ventilated and measurements were taken. MEASUREMENTS AND MAIN RESULTS: At each FIO2, measurements of gas exchange (arterial blood gases and saturation), lung mechanics (mean airway pressure, static end-inspiratory pressure, and peak inspiratory pressure), and hemodynamics (heart rate, and mean arterial, right atrial, pulmonary artery occlusion, and pulmonary arterial pressures) were recorded. In six piglets, cardiac output was measured at each FIO2 by thermodilution. Cardiac index, indexed oxygen delivery and consumption, and indexed pulmonary vascular resistance were derived using standard formulas. Piglets were well saturated at all FIO2 settings during continuous positive-pressure breathing. However, during perfluorocarbon-associated gas exchange, arterial saturation decreased to 72% at an FIO2 of 0.3. Cardiac index and oxygen consumption were not affected by reducing FIO2 during perfluorocarbon-associated gas exchange, and were not significantly different than during continuous positive-pressure breathing. Oxygen delivery was reduced at an FIO2 of 0.3 during perfluorocarbon-associated gas exchange, but oxygen consumption remained in the flow independent portion of the curve despite arterial desaturation. Pulmonary arterial pressure was higher during perfluorocarbon-associated gas exchange than during continuous positive-pressure breathing. Pulmonary arterial pressure and indexed pulmonary vascular resistance were significantly higher during perfluorocarbon-associated gas exchange at an FIO2 of 0.3 than at any other FIO2 settings. CONCLUSIONS: Piglets showed no adverse effects on lung mechanics during perfluorocarbon-associated gas exchange. Hemodynamics were well supported at all FIO2 settings, and arterial blood was fully oxygenated during perfluorocarbon-associated gas exchange at an FIO2 of > or = 0.5.

Perfluorocarbon-associated gas exchange in gastric aspiration.

OBJECTIVES: To test whether perfluorocarbon-associated gas exchange (gas ventilation of the perfluorocarbon-liquid filled lung) could support oxygenation better than conventional positive pressure breathing in a piglet model of gastric aspiration-induced adult respiratory distress syndrome (ARDS). DESIGN: Prospective, randomized, blinded, controlled study. SETTING: A critical care research laboratory in a university medical school. SUBJECTS: Fourteen healthy piglets. INTERVENTIONS: Under alpha-chloralose anesthesia and metocurine iodide neuromuscular blockade, 14 piglets underwent tracheostomy; central venous, systemic and pulmonary arterial catheterizations; and volume-regulated continuous positive-pressure breathing. Homogenized gastric aspirate (1 mL/kg) titrated to pH of 1.0 was instilled into the tracheostomy tube of each subject at 0 min to induce ARDS. Hemodynamics, lung mechanics, and gas exchange were evaluated every 30 mins for 6 hrs. Seven piglets were treated at 60 mins by tracheal instillation of perflubron, a volume selected to approximate normal functional residual capacity, and were supported by perfluorocarbon-associated gas exchange without modifying ventilatory settings. Perflubron was added to the trachea every hour to replace evaporative losses. MEASUREMENTS AND MAIN RESULTS: There was a significant difference in oxygenation over time when tested by repeated-measures analysis of variance (F test = 8.78, p < .01). On further analysis, the differences were not significant from baseline to 2.5 hrs but became increasingly significant from 2.5 to 6 hrs after injury (p < .05) in the inflammatory phase of gastric aspiration-induced ARDS. Histologic evidence for ARDS in the treated group 6 hrs after injury was lacking. CONCLUSIONS: In the piglet model, perfluorocarbon-associated gas exchange with perflubron facilitates oxygenation in the acute phase of gastric aspiration-induced inflammatory ARDS when compared with conventional positive-pressure breathing. Histologic and physiologic data suggest that perfluorocarbon-associated gas exchange with perflubron might prevent ARDS if instituted after aspiration in the time window before the acute inflammatory process is manifest.

Perfluorocarbon associated gas exchange (PAGE): gas ventilation of the perfluorocarbon filled lung.

BACKGROUND: Throughout most of the second half of this century, progress in respiratory life support was dominated by modernization of the mechanical ventilator. We have now entered an era in which the fundamental physiology of lung function can be manipulated to improve lung performance in hope of reducing morbidity and mortality and thereby decreasing the cost of intensive care. MAIN FINDINGS: Despite its almost alien technology, perfluorocarbon tidal liquid breathing is an effective means to support respiration in normal and surfactant deficient lungs. A second, technique, perfluorocarbon associated gas exchange (PAGE), has recently been shown effective in normal lungs and in several animal models of lung disease. Both techniques appear to improve pulmonary function when pulmonary surface tension is elevated. CONCLUSIONS: PAGE improves lung function and poses opportunities to reduce pulmonary morbidity and diminish the cost of intensive care.

Oxygenation during perfluorocarbon associated gas exchange in normal and abnormal lungs.

Perfluorocarbon-associated gas exchange (PAGE) has been proposed for the treatment of lung diseases characterized by high alveolar surface tension. Perflubron (perfluorooctyl bromide, LiquiVent, Alliance Pharmaceutical Corp.) is a high purity medical grade perfluorocarbon suitable for PAGE. We studied PAGE using perflubron in normal piglets and in animal models of pulmonary disease (meconium aspiration syndrome, oleic acid infusion and gastric acid aspiration as models of ARDS, and neonatal respiratory distress syndrome). All animals were studied under anesthesia. PAGE was instituted by intratracheal instillation of a volume of perflubron (generally 30 ml/kg) that approximates a normal functional residual capacity of the lung. Arterial blood gases were measured at 15 minute intervals. FiO2 during PAGE was 1.0. In normal piglets, PaO2 fell from 543 torr (during conventional gas breathing) to 363 torr (during PAGE). However, in models of lung disease, PAGE significantly enhanced PaO2.

A prospective, randomized study of continuous versus intermittent nebulized albuterol for severe status asthmaticus in children.

OBJECTIVES: a) to determine if continuous nebulization of albuterol is more effective than intermittent nebulization in the treatment of children with status asthmaticus and impending respiratory failure; b) to determine the effect of continuous nebulization and intermittent nebulization on duration of hospital stay and bedside respiratory therapy care. DESIGN: Prospective, randomized study. SETTING: A pediatric intensive care unit (ICU) in a university children's hospital. PATIENTS: Seventeen pediatric asthmatic patients with severe status asthmaticus, with impending respiratory failure (Woods asthma score > or = 5), and without evidence of cardiac or other preexisting lung disease were admitted to the pediatric ICU. The patients were randomized to receive continuous nebulization (n = 9) or intermittent nebulization (n = 8) of albuterol. INTERVENTIONS: The asthmatic patients were randomized into two groups. The continuous group received 0.3 mg/kg/hr of albuterol by continuous nebulization; the intermittent group received 0.3 mg/kg of albuterol over 20 mins every hour. All patients received aerosol therapy through the same delivery system. MEASUREMENTS: Responses to therapy were evaluated by following asthma score, arterial blood gas values, hemodynamics, FIO2, and arterial oxygen saturation initially and at 30 mins, 1 hr, 2 hrs, 4 hrs, then every 4 hrs for a 24-hr time period. Patients were determined to no longer be in impending respiratory failure when their asthma score was < 5 for four consecutive hours. Electrocardiograms, serum electrolyte values, and creatine phosphokinase total and MB fraction values were obtained before and after treatment. Hospital stay and respiratory therapy time, in relative value units (one relative value unit = 10 mins) were analyzed from data collected from therapist bedside flow sheets. RESULTS: The patient characteristics (demographics, hemodynamics, arterial blood gas values, asthma severity, corticosteroid use, theophylline, and beta 2-adrenergic receptor agonist administration) before entry into the study did not differ between groups. Patients in the continuous group improved more rapidly and were out of impending respiratory failure sooner than patients in the intermittent group (continuous group = 12 (median) hrs (range 4 to 24) vs. intermittent group = 18 (median) hrs (range 12 to 24; p = .03). Bedside respiratory therapy time evaluated by relative value units was less for patients who received continuous nebulization of albuterol (continuous group = 14 (median) relative value units (range 6 to 26) vs. intermittent group = 33 (median) relative value units (range 25 to 49; p = .001). Hospital stay was shorter for patients who received continuous nebulization of albuterol (continuous group = 80 [median] hrs [range 51 to 173] vs. intermittent group = 147 [median] hrs [range 95 to 256]; p = .043). Hemodynamics, serum potassium, and creatine phosphokinase concentrations did not differ before and after the study in either group. CONCLUSIONS: In children with impending respiratory failure due to status asthmaticus, continuous nebulization of albuterol is safe and results in more rapid clinical improvement than intermittent nebulization. Respiratory therapy required at the bedside and duration of hospital stay were substantially less for patients receiving continuous nebulization of albuterol, which suggests that continuous nebulization of albuterol is more cost effective than intermittent nebulization.