ARTICLE Liquid Ventilation: Current Status Thomas H. Shaffer, PhD*, Marla R. Wolfson, PhD†, Jay S. Greenspan, MD‡ and cancer. For example, therapeutic OBJECTIVES treatment of lung cancer with drugs After reading this article, the reader should be able to: can have devastating effects on other tissues in the body. By using 1. List the potential medical applications of liquid-assisted ventilation LV as a carrier for the drug, adverse (LAV). side effects can be minimized 2. Describe the properties of perfluorochemical liquids that are impor- because the agent is administered tant for their use in liquid ventilation. directly to the surface of the lung. 3. Describe the potential benefits of LAV in respiratory distress Furthermore, recent studies have syndrome, congenital diaphragmatic hernia, acute respiratory distress syndrome, and aspiration syndromes. shown that it is possible to enhance 4. Delineate specific nonrespiratory applications of LAV. high-resolution computed tomogra- phy (HRCT) images of the respira- tory system by administering PFC to the lungs. Finally, as depicted in the Introduction damage of pulmonary tissues and underwater science-fiction novel and With the advent of modern technol- structures from conventional film, The Abyss, liquid breathing has ogy and the evolution of intensive mechanical ventilation (CMV). the potential to allow humans to care units, the ability to treat respi- Of equal importance, acute respi- survive in unusual environments ratory problems has improved ratory distress syndrome (ARDS) such as in great deeps, in space, and remarkably. This accomplishment is due to trauma, aspiration, or infec- under great acceleration. particularly remarkable with respect tion strikes more than 100,000 The biomedical application of to the 40,000 preterm infants born adults in the United States annually. LAV has been explored in animal each year of whom thousands have Despite aggressive therapeutic pro- models for more than 3 decades. severe respiratory problems. Fortu- cedures, 60% to 70% of these patients More recently, clinical investiga- nately, the number of smaller and die, and as in infants, many suffer tional trials have shown that it is more immature infants who are complications associated with CMV. possible to maintain gas exchange in treated, survive respiratory distress, Although structural damage in critically ill neonates, children, and and recover uneventfully is increas- adults or immaturity in infants can- adults using LV. This review dis- ing. However, the overall success of not be altered acutely, current treating neonatal respiratory distress advances, such as exogenous surfac- remains limited by the inherent tant replacement therapy to reduce ABBREVIATIONS problems of surfactant deficiency alveolar interfacial surface tension ARDS: acute respiratory distress and structural immaturity of the and subsequent inflation pressures, syndrome lung. Consequently, infants deliv- have allowed clinical improvement CDH: congenital diaphragmatic ered preterm who have respiratory in gas exchange and decreases in hernia insufficiency experience diminished ventilatory requirements, baro- CMV: conventional mechanical lung distensibility that results in pro- trauma, and mortality. Therefore, it ventilation gressive atelectasis and respiratory appears that the complications asso- ECMO: extracorporeal membrane oxygenation failure requiring mechanical ventila- ciated with respiratory distress can ECLS: extracorporeal life support tion. Currently, many of these be lessened in proportion to the FRC: functional residual capacity infants improve over time when therapeutic reduction of interfacial GV: gas ventilation their ventilation is supported surface tension and ventilatory HFOV: high-frequency oscillatory mechanically and surfactant is intro- requirements. The concept of maxi- ventilation duced into their lungs. However, as mally reducing surface tension has HRCT: high-resolution computed many as 37% of these severely been explored through liquid venti- tomography impaired infants are left with bron- lation (LV) techniques with perfluo- I:E: inspiratory-to-expiratory time chopulmonary dysplasia related to rochemical (PFC) liquids. IL: interleukin In addition to respiratory support, LAV: liquid-assisted ventilation other possible medical applications LPS: lipopolysaccharide *Professor of Physiology and Pediatrics; for liquid-assisted ventilation (LAV) LV: liquid ventilation Director, Respiratory Physiology Section, are being investigated. Liquid in the NMR: nuclear magnetic resonance Temple University School of Medicine, lung can remove debris caused by NO: nitric oxide Philadelphia, PA. cystic fibrosis, alveolar proteinosis, † PFC: perfluorochemical Associate Professor of Physiology and or aspiration syndromes. In addition, Pediatrics, Temple University School of PLV: partial liquid ventilation Medicine, Philadelphia, PA. with the aid of liquid in the lungs, RDS: respiratory distress syndrome ‡Professor of Pediatrics; Director, Section of pharmacologic agents can be admin- TLV: total liquid ventilation Neonatology, Thomas Jefferson University, istered with greater effectiveness in TNF: tumor necrosis factor Philadelphia, PA. lung diseases involving infection e134 NeoReviews December 1999 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 30, 2021 RESPIRATORY DISEASE Liquid Ventilation iments, animals survived for hours if the liquid was oxygenated continu- ally, but the increased work of breathing led to fatigue. Another early technique used gravity-assisted ventilation with oxygenated PFC draining from a reservoir into the lungs of intubated animals. Neither of these early methods proved ade- quate for prolonged ventilation. In an attempt to improve on these tech- niques, the concept of demand- regulated LV was demonstrated by Shaffer and Moskowitz. This tech- nique allowed experimental animals FIGURE 1. Schematic of the perfluorochemical compound perflubron (LiquiVentR; to control the cycling of the respira- Alliance Pharmaceutical, San Diego, CA). This low molecular weight (499; tor that circulates oxygenated liquid C8F17Br) compound is very stable, is biologically inert, and is not metabolized. to and from the lungs. This method established tidal volume and breath- cusses the physiology and methodol- uted with blood flow to body tis- ing frequency requirements and ogy of LAV techniques, the ratio- sues. Because PFC liquid is nearly reduced breathing effort by provid- nale and current status of animal insoluble in water, essentially all of ing mechanical assistance. The early and human experiences, and the the PFC in the blood and tissues is experiments with this type of venti- broad-based potential applications. dissolved in lipid. Extensive studies lation reported effective oxygenation in animals and adult humans have and better removal of carbon diox- examined the physiology, toxicity, ide. This particular device was cited Respiratory Liquids and biodistribution of PFC when explicitly in the novelization of The PFC liquids are fluorinated hydro- used intravascularly as a blood sub- Abyss and formed the conceptual carbons in which the hydrogen stitute. The concentrations of PFC in basis for the deep diving device atoms have been replaced by fluo- the blood after intravascular admin- depicted in the movie. rine atoms; for perflubron a bromine istration were several orders of mag- Experiments with this type of atom is added as well (Fig. 1). nitude greater than any blood or ventilation established the necessary These fluids are stable chemicals tissue level reported following LV. system components as well as tidal that are clear, colorless, odorless, All studies reporting uptake as a volume and breathing frequency and insoluble in water. The dielec- result of LV have shown very low requirements for mechanical ventila- tric strength and heat capacity of the levels of PFC in the blood and tis- tion with liquids. A system for time- PFC fluids are high; they are denser sues. The most current studies report cycled, pressure-limited TLV was than both water and soft tissue, and PFC levels of less than 5.8 mcg/mL developed, and animals of various surface tension and viscosity are of blood. Tissue levels were both gestational ages and lung abnormali- generally low. Certain PFC liquids PFC- and organ-dependent, with the ties were maintained with adequate have higher vapor pressure than lowest levels in the liver and the gas exchange for extended periods water and will evaporate much highest levels in the lung, followed of time. This LV strategy allows for faster than water at body tempera- by fat tissue. Excluding lung and fine control of tidal volume, airway ture. Of particular importance is the fat, tissue levels were less than and alveolar pressure, and functional fact that these liquids have an 250 mg/g of tissue after 24 hours of residual capacity (FRC). Function- exceptionally high gas solubility and LV. PFC is not metabolized and is ally, the system resembles an extra- can dissolve as much as 20 times eliminated intact by evaporation dur- corporeal membrane oxygenation the amount of oxygen and more ing exhalation or transpiration (ECMO) circuit in that it has a than three times as much carbon through the skin. pump to regulate flow, an oxygen- dioxide as water. Oxygen solubility ator (for oxygenation of the expired is two to three times that of whole fluid), a heater, and a condensing blood. In general, PFC fluids are Respiratory Support system to recapture PFC (Fig.