For 350 million years, fish have breathed liquid through gills. Mammals evolved lungs to breathe air. Rarely, circumstances can occur when a mammal needs to ‘turn back the clock’ to breathe through a special liquid medium. This is particularly true if surface tension at the air–liquid interface of the lung is increased, as in acute lung injury. In this condition, surface tension increases because the pulmonary surfactant system is damaged, causing alveolar collapse, atelectasis, increased right-to-left shunt and hypoxaemia.69Ware LB Matthay MA The acute respiratory distress syndrome.New Engl J Med. 2000; 342: 1334-1349Crossref PubMed Scopus (4483) Google Scholar The aims of treatment are: (i) to offset increased forces causing lung collapse by applying mechanical ventilation with PEEP; (ii) to decrease alveolar surface tension with exogenous surfactant; (iii) to eliminate the air–liquid interface by filling the lung with a fluid in which both oxygen and carbon dioxide are highly soluble to serve as a respiratory medium. This third concept, liquid ventilation, recalls the early work of von Neergaard, who showed that the pressure necessary to expand a lung filled with air is almost three times that required to distend a lung filled with liquid.68von Neergaard K Neue Auffassungen bei einem Grundbegriff der Atemmechanik; Die Retraktionskraft der Lungen abhangig von der Oberflachungspannung in den Alveolen.Z Gesarnte Exp Med. 1929; 66: 373-394Crossref Google Scholar After the First World War, basic research in the treatment of poison gas inhalation was carried out using saline solutions applied to the lungs of dogs.70Winternitz MC Smith GH Preliminary studies in intratracheal therapy.in: Pathology of War Gas Poisoning. Yale University Press, Yale1920: 145-160Google Scholar It was Kylstra and colleagues in the 1960s who first showed that mammals could breathe a liquid medium, starting a resurgence of systematic research in this topic.40Kylstra JA Tissing MO van der Maen A Of mice as fish.Trans Am Soc Artif Intern Organ. 1962; 8: 378-383Crossref PubMed Google Scholar At that time, breathing a liquid medium was studied to increase the escape depth from a submerged submarine. These investigators described the immersion of mice in physiological salt solutions. To allow sufficient oxygen to be dissolved in solution, the animals were subjected to increased pressures, in some cases up to 160 atm, which is the pressure 1 mile below the surface of the sea. However, the work of breathing was very great and the animals died within minutes of respiratory acidosis. Thus, liquid breathing was described but to be practicable, a medium that could dissolve large amounts of the respiratory gases at atmospheric pressure was needed. Relatively few agents have these properties – essentially only silicone oils and perfluorocarbons (PFCs). Clark and Gollan7Clark LC Gollan F Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure.Science. 1966; 152: 1755-1766Crossref PubMed Scopus (648) Google Scholar completely immersed small mammals in silicone oils and PFCs. Silicone oils proved to be toxic, and only PFCs remained for possible use.6Clark LC Introduction.Fed Proc. 1970; 29: 1698Google Scholar 62Shaffer TH Wolfson MR Liquid ventilation.Pediatr Pulmonol. 1992; 14: 102-109Crossref PubMed Scopus (199) Google Scholar PFCs were synthesized during the development of the atomic bomb (the Manhattan Project) where they were given the codename ‘Joe's stuff’.6Clark LC Introduction.Fed Proc. 1970; 29: 1698Google Scholar They were synthesized during the search for substances that resisted attack by reactive uranium compounds, particularly uranium hexafluoride.47Lowe KC Perfluorochemical respiratory gas carriers: applications in medicine and biotechnology.Sci Prog. 1997; : 169-193PubMed Google Scholar The PFCs are organic compounds in which all hydrogen atoms have been replaced by halogens, usually fluoride. There are a number of methods for synthesis, such as electrochemical fluorination, heating of organic compounds with cobalt trifluoride, or careful direct fluorination with gaseous fluoride.61Sargent JW Seffl RJ Properties of perfluorinated liquids.Fed Proc. 1970; : 1699-1703PubMed Google Scholar Non-medical uses of PFC include in the cosmetic industry for their water retention properties, as cooling agents and as insulators. In medical applications, besides use as a respiratory medium, PFCs are being evaluated as contrast agents for computerized tomography and magnetic resonance imaging, as sensitizing agents during radiotherapy and as possible i.v. oxygen-carrying agents.62Shaffer TH Wolfson MR Liquid ventilation.Pediatr Pulmonol. 1992; 14: 102-109Crossref PubMed Scopus (199) Google Scholar 48Lowe KC Perfluorinated blood substitutes and artificial oxygen carriers.Blood Rev. 1999; 13: 171-184Abstract Full Text PDF PubMed Scopus (107) Google Scholar PFCs are stable, inert compounds; they do not react with living tissues because of their carbon–fluoride bonds and the electron-rich fluorine substituents protect the underlying carbon skeleton. PFCs also have low intermolecular forces, so the surface tension of these liquids is remarkably low.47Lowe KC Perfluorochemical respiratory gas carriers: applications in medicine and biotechnology.Sci Prog. 1997; : 169-193PubMed Google Scholar Most PFCs have a surface tension of 12–18 dyne cm−1.62Shaffer TH Wolfson MR Liquid ventilation.Pediatr Pulmonol. 1992; 14: 102-109Crossref PubMed Scopus (199) Google Scholar Although nearly twice as dense as water, most PFCs have a similar kinematic viscosity to water. PFCs are immiscible with both hydrophobic and aqueous solutions. Of great interest is that at atmospheric pressure and body temperature, PFCs dissolve large amounts of gases, in particular oxygen and carbon dioxide. Generally, gas solubility in PFCs decreases in the order carbon dioxide >> oxygen > carbon monoxide > nitrogen. Linear PFCs such as Perflubron dissolve more oxygen than cyclic molecules such as Perfluorodecalin48Lowe KC Perfluorinated blood substitutes and artificial oxygen carriers.Blood Rev. 1999; 13: 171-184Abstract Full Text PDF PubMed Scopus (107) Google Scholar (see Fig. 2). However, oxygen solubility is inversely proportional to the molecular weight of the PFC and directly related to the number of fluorine atoms present.48Lowe KC Perfluorinated blood substitutes and artificial oxygen carriers.Blood Rev. 1999; 13: 171-184Abstract Full Text PDF PubMed Scopus (107) Google Scholar Of course, the solution of oxygen in PFCs is an entirely passive process, unlike the binding and release of oxygen to haemoglobin in the blood. Physicochemical properties of selected PFCs are given in Table 1.Table 1Properties of some perfluorocarbon liquids. Data on FC-77, FC-75 and FC-3280 are from the manufacturers’ data sheets and Shaffer and colleagues;62 data on Perfluorodecalin and Perflubron are from Shaffer and colleagues62 and Cox and colleagues.8 Data on Rimar 101 are from Shaffer and colleagues62 and the manufacturer (Miteni, Milan, Italy)FC-77FC-75FC-3280Rimar 101PerfluorodecalinPerflubronChemical formula50/50 mix of two isomers of C8F16O40/40/20 mix of two isomers of C8F16O, and C8F18C8F18C8F16OC10F18C8F17BrMolecular weight (Daltons)Approx. 416Approx. 420438416462499Boiling point (°C)97102102101142143Density at 25 °C (g cc−1)1.781.781.761.771.951.93Kinematic viscocity at 25 °C (centi-stokes)0.800.820.80.822.901.1Vapour pressure at 37 °C (mm Hg)8563Approx. 51641411Surface tension at 25 °C (dyne cm−1)151515151518Oxygen solubility at 25 °C (ml gas per 100 ml liquid)5052Approx. 48524953Carbon dioxide solubility at 37 °C (ml gas per 100 ml liquid)198160Approx. 176160140210 Open table in a new tab Clark and Gollan7Clark LC Gollan F Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure.Science. 1966; 152: 1755-1766Crossref PubMed Scopus (648) Google Scholar reported total immersion of small mammals in PFCs. Use of this novel concept clinically for liquid ventilation required a practical method, which was achieved by instilling PFCs into the respiratory tract. The first liquid ventilation with PFCs in animals was done from a chamber above the animal (under the force of gravity), then draining the liquid into a chamber below the animal.18Gollan F McDermott J Johnson AE Namon R Compliance and diffusion during respiration with fluorocarbon fluid.Fed Proc. 1970; 29: 1725-1730PubMed Google Scholar 29Holaday DA Fiserova-Bergerova V Modell JH Uptake, distribution and excretion of fluorocarbon FX 80 (perfluorobutyl perfluorotetrahydrofuran) during liquid breathing in the dog.Anesthesiology. 1972; 37: 387-394Crossref PubMed Scopus (41) Google Scholar 39Koen P Wolfson MR Shaffer TH Fluorocarbon ventilation: maximum expiratory flows and CO2 elimination.Pediatr Res. 1988; 24: 291-296Crossref PubMed Scopus (77) Google Scholar 62Shaffer TH Wolfson MR Liquid ventilation.Pediatr Pulmonol. 1992; 14: 102-109Crossref PubMed Scopus (199) Google Scholar 71Wolfson MR Greenspan JS Deoras KS Rubenstein DS Comparison of gas and liquid ventilation: clinical, physiological and histological correlates.J Appl Physiol. 1992; 72: 1024-1031PubMed Google Scholar In another method, liquid ventilation was performed with an extracorporeal circuit.25Hirschl RB Merz SI Montoya JP et al.Development and application of a simplified liquid ventilator.Crit Care Med. 1995; 23: 157-163Crossref PubMed Scopus (62) Google Scholar 55Moskowitz GD A mechanical ventilator for control of liquid breathing.Fed Proc. 1970; 5: 1751-1752Google Scholar These methods, when the subject is administered a liquid tidal volume, are termed total liquid ventilation. However, the technique is cumbersome and needs complex equipment (Fig. 1). In particular, the extracorporeal circuit had problems in development, in particular malfunction of the expiratory valve. Over the last 40 years, liquid ventilation has been studied in various animal models: normal, premature and with lung injury.18Gollan F McDermott J Johnson AE Namon R Compliance and diffusion during respiration with fluorocarbon fluid.Fed Proc. 1970; 29: 1725-1730PubMed Google Scholar 26Hirschl RB Parent A Tooley R et al.Liquid ventilation improves pulmonary function, gas exchange and lung injury in a model of respiratory failure.Ann Surg. 1995; 221: 79-88Crossref PubMed Scopus (149) Google Scholar 29Holaday DA Fiserova-Bergerova V Modell JH Uptake, distribution and excretion of fluorocarbon FX 80 (perfluorobutyl perfluorotetrahydrofuran) during liquid breathing in the dog.Anesthesiology. 1972; 37: 387-394Crossref PubMed Scopus (41) Google Scholar 39Koen P Wolfson MR Shaffer TH Fluorocarbon ventilation: maximum expiratory flows and CO2 elimination.Pediatr Res. 1988; 24: 291-296Crossref PubMed Scopus (77) Google Scholar 59Saga S Modell JH Calderwood HW et al.Pulmonary function after ventilation with fluorocarbon liquid P-12F (Caroxin F).J Appl Physiol. 1973; 34: 160-164PubMed Google Scholar 62Shaffer TH Wolfson MR Liquid ventilation.Pediatr Pulmonol. 1992; 14: 102-109Crossref PubMed Scopus (199) Google Scholar 71Wolfson MR Greenspan JS Deoras KS Rubenstein DS Comparison of gas and liquid ventilation: clinical, physiological and histological correlates.J Appl Physiol. 1992; 72: 1024-1031PubMed Google Scholar Studies in animals with normal lungs showed worse gas exchange with liquid ventilation compared with gas ventilation.15Fuhrman BP Paczan PR DeFrancis M Perfluorocarbon associated gas exchange.Crit Care Med. 1991; 19: 712-722Crossref PubMed Scopus (334) Google Scholar 23Hernan LJ Fuhrman BP Papo MC et al.Cardiorespiratory effects of perfluorocarbon associated gas exchange at reduced oxygen concentrations.Crit Care Med. 1995; 23: 553-559Crossref PubMed Scopus (32) Google Scholar 65Tutuncu AS Houmes RJM Bos JAH Wollmer P Lachmann B Evaluation of lung function after intratracheal perfluorocarbon administration in healthy animals.Crit Care Med. 1996; 24: 274-279Crossref PubMed Scopus (66) Google Scholar In healthy lungs, oxygenation is impaired during liquid ventilation because the distribution of ventilation/perfusion ratios is changed and there is the imposition of an additional diffusion barrier to oxygen.49Mates EA Hildebrandt J Jackson JC Tarczy-Hornoch P Hlastala MP Shunt and ventilation-perfusion distribution during partial liquid ventilation in healthy piglets.J Appl Physiol. 1997; 82: 933-942PubMed Google Scholar In addition, lung mechanics are disturbed during liquid ventilation in healthy animals.65Tutuncu AS Houmes RJM Bos JAH Wollmer P Lachmann B Evaluation of lung function after intratracheal perfluorocarbon administration in healthy animals.Crit Care Med. 1996; 24: 274-279Crossref PubMed Scopus (66) Google Scholar In 1989, Greenspan and colleagues19Greenspan JS Wolfson MR Rubenstein DS Shaffer TH Liquid ventilation of preterm baby.Lancet. 1989; 2: 1095Abstract PubMed Scopus (53) Google Scholar used a liquid-ventilation technique with the PFC, Rimar 101, in a 28-week-gestation baby. Conventional ventilation was failing, so ventilation was interrupted to allow two 3-min periods of total liquid ventilation, separated by 15 min. Pre-oxygenated Rimar 101 was given from a burette suspended above the patient, retained in the lungs for 15 s and then drained under gravity into a burette below the patient. A case series of three babies of 23–28 weeks’ gestation, including this first one, was reported the following year.20Greenspan JS Wolfson MR Rubenstein D Shaffer TH Liquid ventilation of human preterm neonates.J Pediatr. 1990; 117: 106-111Abstract Full Text PDF PubMed Scopus (223) Google Scholar Lung compliance improved in all three and oxygenation in two. Thus, liquid ventilation appeared to have clinical potential. Although all three neonates died within 19 h, this was thought to reflect the severity of the clinical condition, rather than a failure of the technique per se. In 1991, Fuhrman and colleagues15Fuhrman BP Paczan PR DeFrancis M Perfluorocarbon associated gas exchange.Crit Care Med. 1991; 19: 712-722Crossref PubMed Scopus (334) Google Scholar described a hybrid technique which they named PFC-associated gas exchange. They filled the lungs of normal piglets to functional residual capacity (FRC) with FC-77, and superimposed tidal volumes with gas upon this. This technique has since become known as partial liquid ventilation (PLV). Hirschl and co-workers27Hirschl RB Pranikoff T Gauger P Schreiner RJ Dechert R Bartlett RB Liquid ventilation in adults, children and full-term neonates.Lancet. 1995; 346: 1201-1202Abstract PubMed Scopus (201) Google Scholar first reported PLV in a mixed group of 19 adult, paediatric and neonatal patients, in an uncontrolled single-centre study to assess the safety and efficacy of PLV. The patients they recruited were already receiving extracorporeal lung assist (ELA), which could provide gas exchange if the PLV failed. They measured alveolar–arterial oxygen difference and static lung compliance when ELA was not taking place. PLV improved both measures. Fourteen of the patients were successfully weaned off ELA and 11 survived, which was the expected survival rate for patients with severe acute respiratory distress symptom (ARDS). The causes of death were irreversible lung injury (four patients), cerebrovascular accident (one patient), ischaemic encephalopathy after cardiac arrest (one patient) and multiple organ failure (two patients). It was concluded that PLV can be safely used in patients with severe respiratory failure and may improve lung function. Acute lung injury is characterized by pulmonary and endothelial inflammation, which causes permeability oedema; loss and dysfunction of surfactant with atelectasis and reduced pulmonary compliance; hypoxaemia from ventilation/perfusion mismatch, with increased intrapulmonary right-to-left shunt; and pulmonary hypertension.69Ware LB Matthay MA The acute respiratory distress syndrome.New Engl J Med. 2000; 342: 1334-1349Crossref PubMed Scopus (4483) Google Scholar In these circumstances, liquid ventilation may be beneficial since it improves compliance of the injured lung and recruits alveoli by reopening collapsed lung regions, so reducing intrapulmonary right-to-left shunt. In addition, PFCs have anti-inflammatory properties in the alveolar space.10Croce MA Fabian TC Patton JH et al.Partial liquid ventilation decreases the inflammatory response in the alveolar environment of trauma patients.J Trauma. 1998; 45: 273-282Crossref PubMed Scopus (99) Google Scholar The anti-inflammatory effects of liquid ventilation in acute lung injury are from inhibition of neutrophil and macrophage function, and the dilution of inflammatory debris in the airways. The ideal PFC for liquid ventilation should have: (i) a high solubility for oxygen and carbon dioxide to maintain gas exchange; (ii) a greater density than body fluids so that it descends to the dependent regions of the lungs, where most atelectasis occurs, and re-opens them (an effect termed ‘liquid PEEP’); (iii) a low surface tension to compensate for deficient surfactant and improve lung compliance. The vapour pressure of the ideal PFC has to represent a compromise for opposing requirements. If the substance is not volatile, there will be no requirement for it to be constantly replenished. However, because PFCs are inert, elimination from the body is almost entirely by exhalation in the unchanged form; hence, the substance should be sufficiently volatile to allow elimination in an acceptable time. A high vapour pressure will, however, reduce oxygen tension in the open alveoli. Table 1Amato MBP Barbas CSV Medeiros DM et al.Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome.New Engl J Med. 1998; 338: 347-354Crossref PubMed Scopus (2915) Google Scholar gives the characteristics of some PFCs used. In acute lung injury and ARDS, liquid ventilation with PFC may improve oxygenation and lung compliance. The mechanisms of these two effects are different. Several factors may allow improvement in oxygenation. In acute lung injury, collapse is mainly in the dependent regions of the lungs.16Gattinoni L D'Andrea L Pelosi P et al.Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome.JAMA. 1993; 269: 2122-2127Crossref PubMed Scopus (390) Google Scholar 57Pelosi P Crotti S Brazzi L Gattinoni L Computed tomography in adult respiratory distress syndrome: what has it taught us?.Eur Respir J. 1999; 9: 1055-1062Crossref Scopus (110) Google Scholar Because PFCs are dense, they will gravitate to the dependent parts of the lungs.12Doctor A Ibla JC Grenier BM et al.Pulmonary blood flow distribution during partial liquid ventilation.J Appl Physiol. 1998; 84: 1540-1550PubMed Google Scholar 35Kazerooni EA Pranikoff T Cascade PN Hirschl RB Partial liquid ventilation with peflubron during extracorporeal life support in adults: radiographic appearance.Radiology. 1996; 198: 137-142Crossref PubMed Scopus (37) Google Scholar 54Morris KP Cox PN Mazer CD Frndova H McKerlie C Wolfe R Distribution of pulmonary blood flow in the perfluorocarbon-filled lung.Intensive Care Med. 2000; 26: 756-763Crossref PubMed Scopus (36) Google Scholar 58Quintel M Hirschl RB Roth H Loose R van Ackern K Computer tomographic assessment of perfluorocarbon and gas distribution during partial liquid ventilation of acute respiratory failure.Am J Respir Crit Care Med. 1998; 158: 249-255Crossref PubMed Scopus (71) Google Scholar The bulk of the liquid will re-open collapsed regions of lung, acting as liquid PEEP. Ventilation/perfusion relationships may also improve for another reason.42Leach CL Fuhrman BP Morin FC Rath MG Perfluorocarbon associated gas exchange (partial liquid ventilation) in respiratory distress syndrome; a prospective randomized controlled study.Crit Care Med. 1993; 21: 1270-1278Crossref PubMed Scopus (196) Google Scholar 71Wolfson MR Greenspan JS Deoras KS Rubenstein DS Comparison of gas and liquid ventilation: clinical, physiological and histological correlates.J Appl Physiol. 1992; 72: 1024-1031PubMed Google Scholar In PLV, some regions of lung, particularly the non-dependent regions, may be predominantly ventilated with gas.58Quintel M Hirschl RB Roth H Loose R van Ackern K Computer tomographic assessment of perfluorocarbon and gas distribution during partial liquid ventilation of acute respiratory failure.Am J Respir Crit Care Med. 1998; 158: 249-255Crossref PubMed Scopus (71) Google Scholar If pulmonary vessels in dependent lung regions are compressed by PFCs in the alveoli of these regions, blood flow could be diverted towards non-dependent, aerated lung.54Morris KP Cox PN Mazer CD Frndova H McKerlie C Wolfe R Distribution of pulmonary blood flow in the perfluorocarbon-filled lung.Intensive Care Med. 2000; 26: 756-763Crossref PubMed Scopus (36) Google Scholar PLV thus improves matching of ventilation to perfusion.22Hernan LJ Fuhrman BP Kaiser RE et al.Perfluorocarbon associated gas exchange in normal and acid injured sheep.Crit Care Med. 1996; 24: 475-481Crossref PubMed Scopus (79) Google Scholar 58Quintel M Hirschl RB Roth H Loose R van Ackern K Computer tomographic assessment of perfluorocarbon and gas distribution during partial liquid ventilation of acute respiratory failure.Am J Respir Crit Care Med. 1998; 158: 249-255Crossref PubMed Scopus (71) Google Scholar By eliminating the air–liquid interface, PLV is thought to reduce interfacial tension and improve lung compliance. Von Neergaard68von Neergaard K Neue Auffassungen bei einem Grundbegriff der Atemmechanik; Die Retraktionskraft der Lungen abhangig von der Oberflachungspannung in den Alveolen.Z Gesarnte Exp Med. 1929; 66: 373-394Crossref Google Scholar showed in 1929 that greater pressure was needed to expand a lung filled with gas than a lung filled with fluid. The additional force is needed to overcome the surface tension in the alveoli between gas and fluid. The exact pattern of distribution of PFCs in the alveoli during PLV is not yet known. Since elimination of the air–liquid interface in the diseased lung will depend on the volume and distribution of the PFC, it may be that different quantities are needed for optimal effects on lung mechanics compared with optimal effects on oxygenation.64Tutuncu AS Faithful NS Lachmann B Intratracheal perfluorocarbon administration combined with mechanical ventilation in experimental respiratory distress syndrome: Dose-dependent improvement of gas exchange.Crit Care Med. 1993; 21: 962-969Crossref PubMed Scopus (188) Google Scholar Tutunca and colleagues64Tutuncu AS Faithful NS Lachmann B Intratracheal perfluorocarbon administration combined with mechanical ventilation in experimental respiratory distress syndrome: Dose-dependent improvement of gas exchange.Crit Care Med. 1993; 21: 962-969Crossref PubMed Scopus (188) Google Scholar studied rabbits subjected to saline lavage, and found a maximum improvement in lung compliance after Perflubron 3 ml kg−1, but oxygenation continued to improve with doses up to 15 ml kg−1. When surfactant is deficient, this can be explained as follows:41Lachmann B Fraterman A Verbrugge SJC Liquid ventilation.in: Marini JJ Slutsky AS Physiological Basis of Ventilatory Support. Marcel Dekker, New York1998: 1131-1154Google Scholar 67Verbrugge SJC Lachmann B Partial liquid ventilation.Eur Respir J. 1997; 10: 1937-1939Crossref PubMed Scopus (10) Google Scholar a small dose of PFC will allow a thin film of PFC to coat alveoli in contact with the compound. Evaporation of PFC allows the substance to reach the non-dependent, ventilated lung regions, above the fluid level of the PFC. Unlike surfactant, PFC has a constant surface tension. Giving more PFC will therefore not reduce the surface tension any more. In contrast, increasing doses of PFCs will progressively open up atelectatic alveoli by a PEEP-like effect and improve oxygenation. PLV could be added to other treatments intended to improve oxygenation, such as conventional gas PEEP,32Kaisers U Kuhlen R Sommerer A et al.Superimposing positive end-expiratory pressure during partial liquid ventilation in experimental lung injury.Eur Respir J. 1998; 11: 1035-1042Crossref PubMed Scopus (40) Google Scholar inhaled nitric oxide,30Houmes RJM Verbrugge SJC Hendrik ER Lachmann B Hemodynamic effects of partial liquid ventilation with perfluorocarbon in acute lung injury.Intensive Care Med. 1995; 21: 966-972Crossref PubMed Scopus (62) Google Scholar 37Kinsella JP Parker TA Gallan H Sheridan BC Abman SH Independent and combined effects of inhaled nitric oxide, liquid perfluorochemical, and high frequency oscillatory ventilation in premature lambs with respiratory distress syndrome.Am J Respir Crit Care Med. 1999; 159: 1220-1227Crossref PubMed Scopus (47) Google Scholar 66Uchida T Nakazawa K Yokoyama K Makita K Amaha K The combination of partial liquid ventilation and inhaled nitric oxide in severe oleic acid lung injury model.Chest. 1998; 113: 1658-1666Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar exogenous surfactant56Mrozek JD Smith KM Bing DR et al.Exogenous surfactant and partial liquid ventilation; physiologic and pathologic effects.Am J Respir Crit Care Med. 1997; 156: 1058-1065Crossref PubMed Scopus (104) Google Scholar and prone positioning.50Max M Kuhlen R Lopez F Reyle-Hahn SM Baumert JH Rossaint R Combining partial liquid ventilation and prone positioning in experimental acute lung injury.Anesthesiology. 1999; 91: 796-803Crossref PubMed Scopus (26) Google Scholar Although the combined treatments augmented the effects of PLV on gas exchange, no synergism was found. PLV may do more than improve gas exchange and respiratory mechanics – it may also reduce pulmonary inflammation. Slutsky and colleagues34Kawamae K Pristine G Chiumello D Tremblay LN Slutsky AS Partial liquid ventilation decreases serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model.Crit Care Med. 2000; 28: 479-483Crossref PubMed Scopus (53) Google Scholar studied rats with acid aspiration and found that PLV with Perflubron reduced serum tumour necrosis factor-alpha. In mice infected with the respiratory syncytial virus, intranasal application of Perflubron inhibited lung cellular inflammation and reduced activation of nuclear factor kappa B.21Haeberle HA Nesti F Dietrich HJ Gatalica Z Garofalo RP Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibiting chemokine expression and nuclear factor-kappa B activation.Am J Respir Crit Care Med. 2002; 165: 1433-1438Crossref PubMed Scopus (49) Google Scholar In piglets subjected to surfactant wash-out, Merz and colleagues51Merz U Klosterhalfen B Hausler M et al.Partial liquid ventilation reduces release of leukotriene B4 and interleukin-6 in brochoalveolar lavage in surfactant depleted newborn pigs.Pediatr Res. 2002; 51: 183-189Crossref PubMed Scopus (38) Google Scholar found the lowest concentrations of leukotriene-B4 and interleukin-6 in bronchoalveolar lavage fluid after PLV compared with either conventional or high-frequency ventilation, both plus exogenous surfactant. However, lung injury assessed histologically was not different between the groups. Thus, PFCs may have anti-inflammatory actions in the alveolar space, but the molecular mechanisms remain to be clarified. Non-respiratory applications of PFCs are currently under evaluation. Delivery of drugs to the lungs by PFCs appears promising. The high solubility of oxygen and carbon dioxide, low surface tension, and their capacity to enter collapsed lung regions may allow better drug distribution in the diseased lung. PFCs have been studied for delivering antibiotics,73Zelinka MA Wolfson MR Calligaro I et al.A comparison of intratracheal and intravenous administration of gentamicin during liquid ventilation.Eur J Pediatr. 1997; 156: 401-404Crossref PubMed Scopus (34) Google Scholar anaesthetics,36Kimless-Garber DB Wolfson MR Carlsson C Shaffer TH Halothane administration during liquid ventilation.Respir Med. 1997; 91: 255-262Abstract Full Text PDF PubMed Scopus (32) Google Scholar vasoactive substances72Wolfson MR Grenspan JS Shaffer TH Pulmonary administration of vasoactive substances by perfluorochemical ventilation.Pediatrics. 1996; 97: 449-455PubMed Google Scholar and adenovirus-mediated gene transfer.45Lisby DA Ballard PL Fox WW et al.Enhanced distribution of adenovirus mediated gene transfer to lung parenchyma by perfluorochemical liquid.Hum Gene Ther. 1997; 8: 919-928Crossref PubMed Scopus (47) Google Scholar In lambs with injury induced by acid lavage, Cox and colleagues8Cox CA Cullen AB Wolfson MR Shaffer TH Intratracheal administraton of perfluorochemical-gentamicin suspension: a comparison to intravenous administration in normal and injured lungs.Pediatr Pulmonol. 2001; 32: 142-151Crossref PubMed Scopus (18) Google Scholar found that giving a PFC–gentamicin suspension (a 1:4 ratio of a nanocrystal suspension of gentamycin 5 mg kg−1 and a stabilizer PFC) into the trachea during PLV resulted in homogenous lung tissue gentamicin levels at lower plasma levels than after i.v. administration. They concluded that when lung perfusion is impaired, as in pneumonia, tissue concentrations of systemic gentamicin can be reduced, and administration with a PFC suspension as carrier increases tissue delivery and distribution. Further research on the use of PLV to assist drug delivery to the lung is needed. Following the first human studies,17Gauger PG Pranikoff T Schreiner RJ Moler FW Hirschl RB Initial experience with partial liquid ventilation in pediatric patients with acute respiratory distress syndrome.Crit Care Med. 1996; 24: 16-22Crossref PubMed Scopus (180) Google Sc