Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

OBJECTIVE: To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. DESIGN: A prospective, randomized, controlled, in vivo animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty-six New Zealand White rabbits. INTERVENTIONS: Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. MEASUREMENTS AND MAIN RESULTS: Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. CONCLUSIONS: Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and decreased lung damage. However, in this small-animal model of acute lung injury, an open lung strategy with deliberate hypercapnia was associated with significant hemodynamic instability.

A fatal case of gun blue ingestion in a toddler.

Acute selenium poisoning occurs infrequently. The form of selenium encountered plays a great role in toxicity. Several fatalities have been reported and all but I involved ingestion of selenious acid or selenium dioxide. A healthy 22-mo-old male ingested up to 15 ml of Gun Blue solution (selenious acid). Initially he was pink, alert, and combative in the ambulance but his condition rapidly deteriorated. There was no measurable blood pressure, his oxygen saturation was 84% by pulse oximetry, and his mental status deteriorated to require hand ventilation. The child was cyanotic, unresponsive, and without palpable pulses upon presentation. Cardiopulmonary resuscitation was initiated unsuccessfully and was terminated after 35 minutes.

Partial liquid ventilation with perflubron attenuates in vivo oxidative damage to proteins and lipids.

OBJECTIVE: To determine the impact of partial liquid ventilation on the degree of pulmonary damage by reactive oxygen species in a model of acute lung injury caused by systemic endotoxemia. DESIGN: A prospective, controlled, in vivo, animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty New Zealand White rabbits. INTERVENTIONS: Mature rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive either partial liquid ventilation (n = 16) with perflubron (18 mL/kg via endotracheal tube) or conventional mechanical ventilation (n = 16). Both groups were ventilated using similar strategies, with an Fio2 of 1.0 and tidal volume as required to obtain a normal Paco2. Animals were then given 0.9 mg/kg Escherichia coli endotoxin intravenously over 30 mins. Eight uninjured instrumented and mechanically ventilated animals served as controls. Partial liquid ventilation or conventional ventilation was continued for 4 hrs before the animals were killed. Lung homogenates were analyzed for malondialdehyde (MDA) and 4-hydroxy-2(E)-nonenal (4-HNE) concentrations using a colorimetric assay. To assess protein oxidative damage, carbonyl groups in protein side chains were derivatized with 2,4-dinitrophenylhydrazine followed by Western blotting with a dinitrophenylated-specific primary antibody. MEASUREMENTS AND MAIN RESULTS: MDA (713.42+/-662 vs. 1601.4+/-1156 nmol/g protein; p = .023) and MDA plus 4-HNE (1480.24+/-788 vs. 2675.2+/-1628 nmol/g protein; p = .038) concentrations were lower in animals treated with partial liquid ventilation compared with conventionally ventilated animals, respectively. Animals treated with partial liquid ventilation exhibited attenuation of dinitrophenylated-derivatized protein bands by Western blotting, indicating a reduction in protein oxidative damage. The presence of perfluorocarbon did not interfere with the MDA assay when assessed by independent analysis in vitro. Perflubron did not serve as a sink for peroxyl radicals produced in the aqueous phase during separate in vitro oxidation experiments. CONCLUSIONS: Partial liquid ventilation attenuates oxidative damage to lipids and proteins during experimental acute lung injury. This finding is not caused by binding of lipid peroxidation products to perflubron or by the peroxyl radical scavenging properties of perflubron.

Systemic perfluorocarbons suppress the acute lung inflammation after gastric acid aspiration in rats.

UNLABELLED: Perflurocarbons (PFCs) are used during liquid ventilation and as hemoglobin substitutes. PFCs reduce free radical generation and damage to the lung during liquid ventilation. Thus, we examined the effects of parenteral administration of PFCs on lung injury after acid aspiration. Rats were treated with intraperitoneal injection of either FC-77 or IV injection of Fluosol. Controls received intraperitoneal or IV normal saline (NS) before or at the time of injury and then were injured by instillation of NS + HCl (pH = 1.25) into their lungs via a tracheotomy. The animals were exposed to air or 98% oxygen, breathing spontaneously. The rats were injected with 0.05 microCi of (125)I-albumin (bovine serum albumin) before injury. The extent of lung injury was assessed 5 h postinjury by compliance and lung albumin permeability index measurement. Myeloperoxidase (MPO) activity and histologic examination were used to assess neutrophilic infiltration. Both FC-77 and Fluosol decreased the permeability index compared with controls (1.05 +/- 0.08; 1.08 +/- 0. 12, respectively, versus 1.34 +/- 0.21) and improved lung compliance after intratracheal instillation of 1.2 mL/kg of HCl/NS, pH = 1.25 + hyperoxia injury (P < 0.05). Lung MPO activity decreased in the FC-77 group and was associated with a concomitant decrease in neutrophil infiltration. MPO activity of the spleen increased after FC-77 treatment. The administration of FC-77 decreased the severity of lung permeability changes associated with acid in the presence or absence of hyperoxia exposure. These data suggest that attenuation of neutrophilic infiltration by PFCs decreases lung injury. IMPLICATIONS: Intraperitoneally administered perfluorocarbons in rats attenuate the neutrophilic infiltration in the lung after acid aspiration, thereby decreasing the alveolar protein leakage and improving pulmonary compliance.

Termination of extracorporeal membrane oxygenation for cardiac support.

The determination of when to stop extracorporeal membrane oxygenation (ECMO) rests upon demonstration of the return of adequate cardiac function to support vital organs and permit subsequent recovery. In general, patients with myocardial stun will recover function within several days. Factors that limit recovery include elevated end diastolic pressures leading to marginal myocardial perfusion, ongoing organ damage, massive anasarca, or progressive deterioration in lung function. Following a trial of slow weaning of ECMO support to condition the heart to take over the entire system flow requirements, decannulation can be accomplished in a standard fashion. When weaning is not successful and additional time does not lead to adequate recovery of cardiac function, physicians and nurses must be prepare to realistically advise families regarding such options as cardiac transplantation or withdrawal of support. It is critically important to provide an open and nonjudgmental environment for families to make these difficult decisions. The greatest difficulties involve ethical and emotional decisions that need to be made in a timely fashion to prevent undo burden on the patient when further ECMO support is futile.

Partial liquid ventilation influences pulmonary histopathology in an animal model of acute lung injury.

PURPOSE: The aim of this study was to assess the effect of partial liquid ventilation (PLV) and conventional mechanical ventilation (CMV) in the pattern of distribution of lung injury in a rabbit model of acute lung injury. MATERIALS AND METHODS: Animals (1.5 to 3.5 kg) were assigned to receive CMV (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O) or PLV with 18 mL/kg of intratracheal perflubron (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O). Lung injury was elicited by intravenous administration of Escherichia coliendotoxin. Uninjured animals ventilated as the CMV group served as controls. After 4 hours of mechanical ventilation, the lungs were removed and tissue injury was assessed by light microscopy using a scoring system. RESULTS: Animals in the CMV group had higher lung injury scores in comparison to the PLV group (10+/-4.5 vs. 5+/-3.3, respectively, P < .05). The injury scores were similar for nondependent lung regions (CMV: 8+/-4.3, PLV: 6+/-2.9) but significantly different for the dependent regions (CMV: 12+/-4.6, PLV: 5+/-3.8, P< .05). CONCLUSIONS: PLV is associated with significant attenuation of lung injury, in comparison to CMV. This effect is predominantly due to attenuation of injury in the dependent region of the lung.

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.

Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits.

Initiation of extracorporeal membrane oxygenation (ECMO) in septic children with severe respiratory failure often improves oxygenation but not pulmonary function. The factors affecting pulmonary function following onset of ECMO are not completely understood, but are thought to involve injury mediated, in part, by reactive oxygen species. We hypothesized that induction of ECMO using 100% oxygen as the sweep gas through the oxygenator would increase lipid peroxidation in endotoxin-primed animals after severe hypoxia. We further speculated that provision of oxygenated blood to the pulmonary circulation via venovenous ECMO would promote a greater degree of oxidative damage to the lung as compared to venoarterial ECMO. Eighteen New Zealand White rabbits were assigned to a control group (control) or two intervention groups subjected to 60 min of venoarterial or venovenous ECMO. ECMO was initiated following an intravenous challenge with 0.5 mg/kg of E. coli endotoxin and a period of global hypoxia leading to an arterial pH of 6.99 +/- 0.09, PaCO2 of 103 +/- 31 mmHg and PaO2 of 27 +/- 5 mmHg. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in lung tissue homogenates and in arterial plasma. Lung tissue MDA demonstrated a strong trend towards an increase in the venoarterial group (1884 +/- 945 nmol/g protein) and in the venovenous group (1905 +/- 758 nmol/g protein) in comparison to the control group (644 +/- 71 nmol/g protein) (p = 0.1; significance at 95% in Scheffe test). Lung tissue MDA in the venovenous group had a significant correlation with mean PaO2 during ECMO by regression analysis (r2 = 0.678, p = 0.044). The change in blood MDA concentration between pre-ECMO and post-ECMO values was greater in the venovenous group (pre 1.62 +/- 0.61 versus post 5.12 +/- 0.2.07 mumol/l, p = 0.043) compared with that seen in the venoarterial group (pre 1.46 +/- 0.38 versus post 3.9 +/- 0.93 mumol/l). Our data support the hypothesis that initiation of ECMO with a circuit gas oxygen concentration of 100% after global hypoxia enhances oxidative damage to lipids in endotoxin-challenged animals. During venovenous ECMO this finding is dependent on PaO2.

The risk of nosocomial pneumonia is not increased during partial liquid ventilation.

OBJECTIVE: To determine whether partial liquid ventilation (PLV) affects the risk of nosocomial pneumonia. STUDY DESIGN: To assess in vitro bacterial adhesion and viability after liquid perfluorocarbon exposure and to assess bacterial recovery after partial liquid ventilation in vivo in rabbits. SETTING: University animal research facility. SUBJECTS: Thirty-six New Zealand White rabbits. INTERVENTIONS: To assess adhesions, radiolabeled Escherichia coli were exposed to perfluorocarbon, incubated against artificial biosurfaces, and compared with nonexposed controls. Bacterial viability in vitro was assessed by exposing broth suspensions of Pasteurella multocida to perflubron for various times. Controls were run in parallel without exposure. Quantitative cultures were performed to determine viability. We undertook short-term and recovery in vivo investigations. The lungs of treated animals were filled with perflubron (approximately 18 mL/kg), and the control rabbits were ventilated without perflubron in an identical fashion. Cryopreserved aliquots of P. multocida were administered via an endotracheal tube. The short-term study animals were ventilated for 6 hrs before being killed. The recovery animals were ventilated for 2-4 hrs, extubated, and killed 20 hrs later. The lungs were removed, aseptically minced, and homogenized. Serial dilutions of the homogenate were quantitatively cultured by manual counting of colonies on agar plates. The recovered organisms were typed for species by the clinical microbiology laboratory. MEASUREMENTS AND MAIN RESULTS: The adhesion of bacteria to immobilized bronchoalveolar lavage and human saliva, respectively, was reduced by 65%+/-7% and 66%+/-1% (p < .05; n = 5) after exposure to perflubron and by 63%+/-9% and 68%+/-6% after exposure to FC-77 (p < .05; n = 5); however, adhesion was not affected by exposure to Rimar. There was no difference in bacterial viability between the control and perflubron-exposed bacteria (n = 5). The in vivo study demonstrated a ten-fold or greater reduction in the number of recovered bacteria in the partial liquid ventilated group compared with the control group. CONCLUSIONS: This study suggests that different perfluorocarbons affect adhesions differently. Perflubron and FC-77 appear to decrease bacterial adhesion, whereas Rimar does not. Rerflubron does not have a direct bactericidal effect. Furthermore, PLV with perflubron decreased the number of viable bacteria per gram of tissue after an intentional inoculation of the airway, suggesting that the risk of nosocomial pneumonia is unlikely to be increased during PLV and may, in fact, be reduced in patients supported with PLV.

Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic endotoxemia and acute lung injury.

OBJECTIVE: To determine whether pulmonary neutrophil sequestration and lung injury are affected by partial liquid ventilation with perfluorocarbon in a model of acute lung injury (ALI). DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: An animal research facility of a health sciences university. SUBJECTS: Forty-one New Zealand White rabbits. INTERVENTIONS: Mature New Zealand White rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive partial liquid ventilation (PLV, n = 15) with perflubron (18 mL/kg via endotracheal tube), conventional mechanical ventilation (CMV, n = 15) or high-frequency oscillatory ventilation (HFOV, n = 5). Animals were ventilated, using an FIO2 of 1.0, and ventilatory settings were required to achieve a normal PaCO2. Animals were then given 0.9 mg/kg of Escherichia coli endotoxin intravenously over 30 mins. Partial liquid ventilation, conventional mechanical ventilation, or high-frequency oscillatory ventilation was continued for an additional 4 hrs before the animals were killed. A group of animals not challenged with endotoxin underwent conventional ventilation for 4.5 hrs, serving as the control group (control, n = 6). Lungs were removed and samples were frozen at -70 degrees C. Representative samples were stained for histology. A visual count of neutrophils per high-power field (hpf) was performed in five randomly selected fields per sample in a blinded fashion by light microscopy. Lung samples were homogenized in triplicate in phosphate buffer, ultrasonified, freeze-thawed, and clarified by centrifugation. Supernatants were analyzed for myeloperoxidase (MPO) activity by spectrophotometry with o-dianisidine dihydrochloride and hydrogen peroxide at 460 nm. MEASUREMENTS AND MAIN RESULTS: Histologic analysis of lung tissue obtained from control animals showed normal lung architecture. Specimens from the PLV and HFOV groups showed a marked decrease in alveolar proteinaceous fluid, pulmonary vascular congestion, edema, necrotic cell debris, and gross inflammatory infiltration when compared with the CMV group. Light microscopy of lung samples of animals supported with PLV and HFOV had significantly lower neutrophil counts when compared with CMV (PLV, 4 +/- 0.3 neutrophils/hpf; HFOV, 4 +/- 0.5 neutrophils/hpf; CMV, 10 +/- 0.9 neutrophils/hpf; p < .01). In addition, MPO activity from lung extracts of PLV and HFOV animals was significantly lower than that of CMV animals (PLV, 61 +/- 13.3 units of MPO activity/lung/kg; HFOV, 43.3 +/- 6.8 units of MPO activity/lung/kg; CMV, 140 +/- 28.5 units of MPO activity/lung/kg; p < .01). MPO activity from lungs of uninjured control animals was significantly lower than that of animals in the PLV, HFOV, and CMV groups (control, 2.2 +/- 2 units of MPO activity/lung/kg; p < .001). CONCLUSIONS: Partial liquid ventilation decreases pulmonary neutrophil accumulation, as shown by decreased neutrophil counts and MPO activity, in an experimental animal model of ALI induced by systemic endotoxemia. The attenuation in pulmonary leukostasis in animals treated with PLV is equivalent to that obtained by a ventilation strategy that targets lung recruitment, such as HFOV.

Comparative effects of lipopolysaccharide on newborn versus adult rat hepatocyte and nonparenchymal cell cocultures.

OBJECTIVE: To examine the effects of development on the response of hepatocytes and nonparenchymal cells to an endotoxin challenge as an in vitro model of organ system dysfunction at differing developmental ages. DESIGN: In vitro animal cell culture model. SETTING: University teaching hospital research laboratory. SUBJECTS: Adult and newborn Sprague-Dawley rats. INTERVENTIONS: The method of hepatocyte and nonparenchymal cell coculture was utilized and modified to allow evaluation of cells derived from newborns. Cells were isolated from adult rats by standard perfusion technique. Hepatocytes and nonparenchymal cells were isolated from newborn rats by use of identical enzymatic degradation after fine mincing of the organ. Isolated cells were purified by density gradient. The hepatocytes were incubated in standard cell culture plates for 24 hrs before the addition of nonparenchymal cells. Hepatocytes were incubated with similar-age nonparenchymal cells. After an additional 24 hrs, serial log dilutions of lipopolysaccharide were added as a stimulus and the system was cultured an additional 24 hrs. The response of the hepatocytes was assessed by determination of 3H-leucine incorporation in acid-precipitated protein. In addition, the production of tumor necrosis factor, interleukin (IL)-1, and IL-6 by isolated nonparenchymal cells from adult and newborn rats was determined after stimulation with serial log dilutions of lipopolysaccharide by bioassay. MEASUREMENTS AND MAIN RESULTS: Both adult and newborn hepatocytes cocultivated with nonparenchymal cells demonstrated a comparable and statistically significant dose response to lipopolysaccharide (p < .01). The newborn hepatocytes demonstrated a greater rate of protein synthesis than the adult hepatocytes at all concentrations of lipopolysaccharide. Tumor necrosis factor production by newborn and adult nonparenchymal cells was similar at all lipopolysaccharide doses. IL-1 production demonstrated a positive dose response to lipopolysaccharide in the adult and newborn nonparenchymal cells, with a trend (p = .17) toward greater IL-1 secretion by the adult cells. There were significant differences in IL-6 production by isolated nonparenchymal cells at lipopolysaccharide doses of 0.01, 0.1, and 10 micrograms/mL. While a similar trend was apparent in the cocultured cells, the significance was not apparent, except at the highest lipopolysaccharide dose. CONCLUSIONS: The dose responses of newborn and adult hepatocytes to nonparenchymal cells stimulated with lipopolysaccharide were similar, although newborn hepatocytes appeared to have an inherently higher rate of protein synthesis compared with adult hepatocytes. Cytokine production was similar in nonparenchymal cells of both ages, although IL-1 production by stimulated newborn nonparenchymal cells appeared to be less than IL-1 production by adult nonparenchymal cells.

Partial liquid ventilation enhances surfactant phospholipid production.

OBJECTIVE: To study the effect of partial liquid ventilation on phospholipid metabolism. DESIGN: Prospective, controlled laboratory study. SETTING: University-affiliated animal research facility. SUBJECTS: Mature New Zealand white rabbits (n = 17). INTERVENTIONS: The rabbits were sedated, anesthetized, and instrumented with tracheostomy and the insertion of an arterial catheter. The rabbits were sequentially assigned to receive conventional mechanical ventilation or partial liquid ventilation with Perflubron (18 mL/kg by bolus fill). Ventilator strategies were identical in both groups and consisted of an FiO2 of 0.5, positive end-expiratory pressure of 4 cm H2O, effective tidal volume of 8 to 13 mL/kg, and rate to maintain Pco2 of 30 to 40 torr (4.0 to 5.3 kPa). Phosphatidylcholine was labeled in vivo by injection of 3H-methylcholine (25 microCi/kg iv). Ventilation was continued for 5.5 hrs. MEASUREMENTS AND MAIN RESULTS: When animals were killed, phosphatidylcholine was extracted from the total lung lavage and from the pulmonary parenchyma. After the separation of phospholipids by thin-layer chromatography, the 3H activity was determined by liquid scintillation counting. Inorganic phosphorus was also determined to assess the enrichment of the phosphatidylcholine. The 3H-phosphatidylcholine activity in the partial liquid ventilation treated- vs. control rabbits demonstrated a 53% increase (p = .051) in the lavage and a 48% increase (p = .013) in the parenchyma for a net 50% (p = .012) total pulmonary increase. The phospholipid content of the partial liquid ventilation treated- vs. the control rabbits demonstrated a 78% increase (p = .046). CONCLUSIONS: We conclude that partial liquid ventilation with Perflubron appears to have no negative impact on phospholipid metabolism but rather enhances surfactant phospholipid synthesis and secretion.

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.

A liquid perfluorochemical decreases the in vitro production of reactive oxygen species by alveolar macrophages.

OBJECTIVE: To determine whether reactive oxygen metabolite production by alveolar macrophages is affected by liquid perfluorochemical exposure. DESIGN: Controlled, animal laboratory investigation of alveolar macrophage function in vitro. SETTING: Animal research facility of a health sciences university. SUBJECTS: Six adult male New Zealand white rabbits and six young piglets. INTERVENTIONS: Alveolar macrophages were obtained after sacrifice from both species by total lung lavage. Macrophages were divided into control and experimental groups. Macrophages in the experimental groups were exposed to perfluorooctylbromide. To determine production of reactive oxygen metabolites, hydrogen peroxide production and chemiluminescence were measured in both experimental and control groups after chemical stimulation. MEASUREMENTS AND MAIN RESULTS: Perfluorooctylbromide-exposed alveolar macrophages produced significantly less hydrogen peroxide (1.4 +/- 1.5 vs. 2.4 +/- 1.6 nmol/10(6) cells; p = .002). Perfluorooctylbromide-exposed alveolar macrophages demonstrated significantly less chemiluminescence activity compared with nonexposed cells (0.70 +/- 0.2 vs. 1.5 +/- 0.2 mV of relative activity per 3.5 x 10(5) cells; p = .005). CONCLUSIONS: Exposure of alveolar macrophages to perfluorooctylbromide in vitro decreases the responsiveness of macrophages to potent stimuli. This finding may partially explain the decrease in pulmonary inflammation seen in animals treated with partial liquid ventilation during experimentally induced lung injury.

Neuromuscular blockade provides no benefit over adequate sedation in ventilated dogs.

PURPOSE: To investigate the effect of pharmacological paralysis on systemic oxygen consumption to determine whether pharmacological paralysis offers a physiological benefit over adequate sedation in ventilated animals. METHODS: Nine dogs with normal pulmonary function were mechanically ventilated and sedated with alpha-chloralose while paralysis was induced with vecuronium. Oxygen consumption was determined via indirect calorimeter in each animal repeatedly in the presence or absence of paralysis with seven paired observations in each animal. Sixty-three pairs of data from nine animals were analyzed by analysis of variance with correction for multiple comparisons. RESULTS: Oxygen consumption was 4.3% higher in the unblocked state compared with the blocked state (5.39 +/- 0.32 v 5.16 +/- 0.34 mL/kg-min, P < .001). Carbon dioxide production was 3.0% higher in the unblocked state compared with the blocked state (4.92 +/- 0.24 v 4.77 +/- 0.23 mL/kg-min, P < .01). No other physiological effects were noted. CONCLUSIONS: Pharmacological paralysis of mechanically ventilated animals with normal pulmonary function that are sedated and resting comfortably produces a statistically significant reduction in oxygen consumption; however, the magnitude of this change is so small that little genuine clinical benefit would be anticipated.

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.