The potential use of liquid ventilation has been investigated since 1962 when Kylstra evaluated the ability to sustain gas exchange in mice spontaneously breathing saline oxygenated at 6 atmospheres. Clark subsequently demonstrated that spontaneously breathing mice could survive when submerged in perfluorocarbon under normobaric conditions. Perfluorocarbons (PFC) are structurally similar to hydrocarbons with the hydrogens replaced by fluorine. The carbon chains vary in length and an additional moiety often is attached to the molecule which, together, give unique properties to each perfluorocarbon. In general, perfluorocarbons have excellent oxygen and carbon dioxide carrying capacity (50 ml O2/dl and 160-210 ml CO2/dl, respectively). They are clear, odourless, inert fluids which are immiscible in aqueous and most other solutions.
Liquid ventilation-two techniques
Total liquid ventilation (TLV)
The lungs are filled with perfluorocarbon to a volume equivalent to the functional residual capacity (FRC, approximately 30 mL/kg) and a "liquid ventilator" is used to generate tidal breathing with perfluorocarbon. Optimal CO2 clearance is achieved when ventilation is performed at a rate of 4-5 breaths/minute. Typical tidal volumes are in the 15-20 ml/kg range. One of the advantages of TLV is that exudate may be lavaged from the airways in the setting of respiratory failure. In addition, the distribution of perfluorocarbon within the lungs may be more uniform during TLV.
Partial liquid ventilation (PLV)
During PLV, gas ventilation of the perfluorocarbon-filled lungs is performed using a standard gas mechanical ventilator. This is a relatively simple technique which does not require use of a specialized device. The adequacy of perfluorocarbon dose is assessed during PLV by visually identifying a meniscus of perfluorocarbon within the endotracheal tube at end-expiration. A typical initial dose of perfluorocarbon during PLV is equivalent to FRC or approximately 30 ml/kg.
In the 30 years since the landmark studies by Kylstra and Clark, numerous studies have evaluated the efficacy of liquid ventilation with perfluorocarbon fluids to improve gas exchange and pulmonary function in animal models of respiratory failure. Many of the initial studies were performed in premature, surfactant-deficient animal models of respiratory insufficiency. One important property of perfluorocarbons is that they have a low surface tension of approximately 18 to 19 dynes/cm which allows perfluorocarbons to serve as "surfactant substitutes". Studies in early pre-term animals clearly demonstrated improvement in compliance, gas exchange, and survival during liquid ventilation when compared to gas ventilation. Subsequent research has revealed marked improvements in parameters of gas exchange and pulmonary function during total and partial liquid ventilation, when compared to gas ventilation, in fullterm newborn, pediatric, and adult animal models of respiratory failure. One other finding, is a reduction in the degree of lung injury and inflammatory infiltrate observed during liquid ventilation when compared to gas ventilation in these models of respiratory failure.
Mechanisms of Liquid ventilation
In preterm newborns, gas exchange may be enhanced during liquid ventilation because of a reduction in the alveolar surface tension which is associated with ventilation of the liquid-filled lung. The mechanical lavage associated with total liquid ventilation may have a salutary effect in the setting of ARDS, pneumonia, or meconium aspiration since exudate may be evacuated from the lungs. Perfluorocarbons also enhance alveolar recruitment in the setting of atelectasis. Cross-sectional imaging has revealed that there is homogenous distribution of the ventilating medium during liquid ventilation when compared to gas ventilation. Specifically, the atelectatic, consolidated, dependent regions of the lungs, which contribute greatly to the associated physiologic shunt observed during gas ventilation in the setting of ARDS, are re-inflated during liquid ventilation. It appears that perfluorocarbons enhance recruitment of alveoli in the setting of atelectasis and, because they are relatively dense, have a predilection for the dependent zones of the lungs. This results in re-inflation of dependent, atelectatic segments and more homogenous ventilation of the lungs.
A second effect of the relatively dense perfluorocarbons may be to redistribute blood flow from the dependent to the non-dependent regions of the lung. In so doing, pulmonary blood flow may be redistributed to less severely injured/atelectatic areas of the lungs with associated improvement in ventilation/perfusion matching.
In 1990, the first clinical evaluation of liquid ventilation was reported in three premature, moribund newborns who underwent pulmonary lavage with perfluorocarbons. The response was varied, but the majority of patients demonstrated improvement in gas exchange and pulmonary compliance. A number of centres are currently evaluating the efficacy of liquid ventilation in the setting of respiratory failure in premature newborns, full-term newborns, children, and adults. It is clear that partial liquid ventilation is at an early stage in its clinical evolution, although substantial progress has been made in the development and evaluation of this new method of ventilation. Prospective, randomized, controlled studies which will allow accurate assessment of the safety, efficacy, and relative cost of this technique in adults, children, and premature neonates are underway. It is likely that total liquid ventilation will enter the clinical arena in the near future as some of the technical aspects of device design are refined. The preliminary pre-clinical and clinical experience would suggest that both techniques of liquid ventilation have the potential to play a significant role in enhancing the management and outcome of patients with respiratory failure.
[i] J. A. Kylstra, M. O. Tissing and A. Van der Maen: Of mice as fish. Trans ASAIO 8: 378-383, 1962.[ii] L. C. Clark Jr. and F. Gollan: Survival of Mammals Breathing Organic Liquids Equilibrated With Oxygen at Atmospheric Pressure. Science 20: 1755-1756, 1966.
[ii] T. H. Shaffer, M. R. Wolfson and L. C. Clark Jr.: State of the art review: Liquid Ventilation. Pediatric Pulmonology 14: 102-109, 1992.
[iii] Liquid ventilation in adults, children, and full-term neonates. Hirschl RB, Pranikoff T, Gauger P, Schreiner RJ, Dechert R, Bartlett RH. Lancet. 1995 Nov 4;346(8984):1201-2