Liquid Ventilation: Current Status (1999)

After reading this article, the reader should be able to:With the advent of modern technology and the evolution of intensive care units, the ability to treat respiratory problems has improved remarkably. This accomplishment is particularly remarkable with respect to the 40,000 preterm infants born each year of whom thousands have severe respiratory problems. Fortunately, the number of smaller and more immature infants who are treated, survive respiratory distress,and recover uneventfully is increasing. However, the overall success of treating neonatal respiratory distress remains limited by the inherent problems of surfactant deficiency and structural immaturity of the lung. Consequently, infants delivered preterm who have respiratory insufficiency experience diminished lung distensibility that results in progressive atelectasis and respiratory failure requiring mechanical ventilation. Currently, many of these infants improve over time when their ventilation is supported mechanically and surfactant is introduced into their lungs. However, as many as 37% of these severely impaired infants are left with bronchopulmonary dysplasia related to damage of pulmonary tissues and structures from conventional mechanical ventilation (CMV).Of equal importance, acute respiratory distress syndrome (ARDS)due to trauma, aspiration, or infection strikes more than 100,000 adults in the United States annually. Despite aggressive therapeutic procedures, 60% to 70% of these patients die, and as in infants, many suffer complications associated with CMV.Although structural damage in adults or immaturity in infants cannot be altered acutely, current advances, such as exogenous surfactant replacement therapy to reduce alveolar interfacial surface tension and subsequent inflation pressures,have allowed clinical improvement in gas exchange and decreases in ventilatory requirements,barotrauma, and mortality. Therefore, it appears that the complications associated with respiratory distress can be lessened in proportion to the therapeutic reduction of interfacial surface tension and ventilatory requirements. The concept of maximally reducing surface tension has been explored through liquid ventilation (LV) techniques with perfluorochemical (PFC) liquids.In addition to respiratory support,other possible medical applications for liquid-assisted ventilation (LAV)are being investigated. Liquid in the lung can remove debris caused by cystic fibrosis, alveolar proteinosis,or aspiration syndromes. In addition,with the aid of liquid in the lungs,pharmacologic agents can be administered with greater effectiveness in lung diseases involving infection and cancer. For example, therapeutic treatment of lung cancer with drugs can have devastating effects on other tissues in the body. By using LV as a carrier for the drug, adverse side effects can be minimized because the agent is administered directly to the surface of the lung. Furthermore, recent studies have shown that it is possible to enhance high-resolution computed tomography (HRCT) images of the respiratory system by administering PFC to the lungs. Finally, as depicted in the underwater science-fiction novel and film, The Abyss, liquid breathing has the potential to allow humans to survive in unusual environments such as in great deeps, in space, and under great acceleration.The biomedical application of LAV has been explored in animal models for more than 3 decades. More recently, clinical investigational trials have shown that it is possible to maintain gas exchange in critically ill neonates, children, and adults using LV. This review discusses the physiology and methodology of LAV techniques, the rationale and current status of animal and human experiences, and the broad-based potential applications.PFC liquids are fluorinated hydrocarbons in which the hydrogen atoms have been replaced by fluorine atoms; for perflubron a bromine atom is added as well (Fig. 1). These fluids are stable chemicals that are clear, colorless, odorless,and insoluble in water. The dielectric strength and heat capacity of the PFC fluids are high; they are denser than both water and soft tissue, and surface tension and viscosity are generally low. Certain PFC liquids have higher vapor pressure than water and will evaporate much faster than water at body temperature. Of particular importance is the fact that these liquids have an exceptionally high gas solubility and can dissolve as much as 20 times the amount of oxygen and more than three times as much carbon dioxide as water. Oxygen solubility is two to three times that of whole blood. In general, PFC fluids are nontoxic and biochemically inert. In addition, they are radiopaque. More than 100 different PFC liquids exist,although only a few commercially available liquids meet both the physicochemical property requirements and purity specifications for respiratory applications.PFC liquids diffuse from the lung into the circulation and are distributed with blood flow to body tissues. Because PFC liquid is nearly insoluble in water, essentially all of the PFC in the blood and tissues is dissolved in lipid. Extensive studies in animals and adult humans have examined the physiology, toxicity,and biodistribution of PFC when used intravascularly as a blood substitute. The concentrations of PFC in the blood after intravascular administration were several orders of magnitude greater than any blood or tissue level reported following LV. All studies reporting uptake as a result of LV have shown very low levels of PFC in the blood and tissues. The most current studies report PFC levels of less than 5.8 mcg/mL of blood. Tissue levels were both PFC- and organ-dependent, with the lowest levels in the liver and the highest levels in the lung, followed by fat tissue. Excluding lung and fat, tissue levels were less than 250 mg/g of tissue after 24 hours of LV. PFC is not metabolized and is eliminated intact by evaporation during exhalation or transpiration through the skin.Several techniques have been investigated for using PFC liquids as a respiratory support medium. Early work with PFC breathing in animals employed total immersion of several small animal species. In these experiments, animals survived for hours if the liquid was oxygenated continually, 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 adequate for prolonged ventilation. In an attempt to improve on these techniques, the concept of demand-regulated LV was demonstrated by Shaffer and Moskowitz. This technique allowed experimental animals to control the cycling of the respirator that circulates oxygenated liquid to and from the lungs. This method established tidal volume and breathing frequency requirements and reduced breathing effort by providing mechanical assistance. The early experiments with this type of ventilation reported effective oxygenation and better removal of carbon dioxide. This particular device was cited explicitly in the novelization of The Abyss and formed the conceptual basis for the deep diving device depicted in the movie.Experiments with this type of ventilation established the necessary system components as well as tidal volume and breathing frequency requirements for mechanical ventilation with liquids. A system for time-cycled, pressure-limited TLV was developed, and animals of various gestational ages and lung abnormalities were maintained with adequate gas exchange for extended periods of time. This LV strategy allows for fine control of tidal volume, airway and alveolar pressure, and functional residual capacity (FRC). Functionally, the system resembles an extracorporeal membrane oxygenation(ECMO) circuit in that it has a pump to regulate flow, an oxygenator (for oxygenation of the expired fluid), a heater, and a condensing system to recapture PFC (Fig. 2). Because PFC liquids have a high heat capacity, the patient’s body temperature can be regulated easily and closely by the liquid temperature during ventilation.Over the years, the liquid ventilator has been refined sufficiently to allow computer operation using the same control modes as gas ventilators; that is, it is time-cycled and can be pressure- or volume-limited,have the inspiratory-to-expiratory time (I:E) ratio be changed, and have the waveform altered. Many of the same general principles used for gas ventilation are applied during LV. The ventilatory rate generally remains constant at 5 breaths/min during TLV (due to longer diffusion times of gases through liquids), and the tidal volume is used to regulate minute ventilation and, therefore,Paco2. With a time-cycled system,tidal volume is regulated by changing flow rates or pressure limits. Unlike gas ventilation (GV), TLV allows unique control and measurement of FRC by monitoring the change in weight as liquid is exchanged between the subject and the LV system. FRC and inspired oxygen concentration can be adjusted to optimize oxygenation. All manipulations can be made within the boundaries of set pressure, volume, and flow limits.Because initial TLV studies demonstrated residual improvements in respiratory function after a return to GV, it was suggested that the administration of PFC liquid to the lungs may function similarly to an artificial surfactant for respiratory distress syndrome (RDS) or a lavage medium for certain other types of pulmonary dysfunction. More recently, several investigators have explored tracheal instillation of PFC liquids in combination with GV in a variety of neonatal, juvenile, and adult animals as well as in preterm human infants and adults who have respiratory failure. Currently, this combined ventilation scheme with PFC liquids and GV is known as PLV and is characterized by filling and sustaining the lung with a volume of PFC liquid less than or equal to the FRC while conventional GV is maintained (Fig. 3). It has been proposed that residual PFC is oxygenated and carbon dioxide is exchanged in the lung by means of the tidal gas movement provided by GV. During PLV, the air-liquid interface in the lungs is not eliminated completely, so some of the major mechanical advantages of a liquid-liquid interface may not be appreciated. However, this technique offers specific advantages over GV for many pulmonary disorders,particularly where surfactant therapy is not an option.A number of techniques have been explored for LAV. Thus far,investigators have considered continuous TLV, brief periods (3 to 5 min) of TLV, rapid instillation of a bolus (30 mL/kg) of oxygenated PFC, and a slow infusion of unoxygenated PFC in doses up to 30 mL/kg over 15 minutes. The optimum PFC filling strategy and the effect of any subsequent GV scheme, including high-frequency,assist-controlled, synchronized, and spontaneous breathing strategies, are still under extensive investigation.It has been reported that the addition of small amounts of PFC liquid(3 mL/kg) to high-frequency oscillatory ventilation (HFOV) resulted in a more rapid improvement in oxygenation for lung-injured piglets compared with HFOV alone(piston-driven). Although oxygenation improved over time in both groups with HFOV, increasing doses of PFC did not result in any significant differences in oxygenation compared with HFOV alone. Neither values for Pco2 and pH nor cardiovascular stability differed between groups. The combination of HFOV and small-dose PFC liquid may permit more effective oxygenation at lower mean airway pressures by facilitating alveolar expansion and decreasing intrapulmonary shunt.Preterm infants characteristically have homogeneous surfactant deficiency and immature parenchyma and initially present with a purely restrictive lung disease that leads quickly to atelectasis. The use of surfactant replacement therapy and prenatal steroids has substantially improved the clinical course of these infants, but they seem to have the most to gain from LAV, particularly when applied early. Surface tension forces are reduced or eliminated,atelectasis is prevented or remedied,and the liquid environment of the developing fetal lung can be reproduced. The need for excessive ventilator pressures and inspired oxygen concentrations is diminished. Multiple animal studies over the years have demonstrated significant improvements in pulmonary mechanics, gas exchange, and histology in models of premature lung disease (Fig. 4).The newborn who has CDH faces the dilemma of pulmonary hypoplasia potentially complicated by surfactant deficiency. PFC liquids have the potential to maximize recruitment of the hypoplastic lung while minimizing the surface tension forces related to surfactant more ventilation and of of a of CDH supported with PLV, at or after a of improved gas exchange and compared with conventional GV. The with PFC liquid at demonstrated improved function compared with infants, and adults all can present with they are or are for they have lungs with an aggressive and Therefore, they potentially can be by lung recruitment and improved Multiple studies have shown the ability of LAV to improve gas and stability in both animal models and neonatal animal models of who have aspiration can from the ability of PFC liquids to support pulmonary and gas exchange while the lung. PFC liquid has been used to that have In these gas and low pulmonary were present during during subsequent was in the expired were during TLV and PLV in oxygen and pulmonary and pulmonary blood flow was more on these it was that TLV improved pulmonary and drugs through the is not a concept for intensive care of pulmonary of agents to the lung. The of the lung as an for agents surface and to the of an agent directly to the lung advantages for and the concept has led not only to to various methods for of drugs during ventilation. In the lung supported with pulmonary blood flow is distributed more and is more exchange can be supported during pulmonary in the lung, and the liquid any between the agent being delivered and the by which it is studies using LAV in preterm that and lung-injured have demonstrated the of using LV techniques to and agents to the lung, including and for Because are not in PFC the success of this for and has on flow and during A technology the to the solubility of agents by in a PFC liquid (Fig. This has been shown to therapeutic levels and higher and more pulmonary concentrations of in and lung-injured neonatal animals than when delivered within the initial of PFC or during In addition to the has been delivered in PFC liquid and was to in experimental animals while gases well to this type of studies have demonstrated to inspired during The ability to during PLV is related to recruitment of lung of in the of the lung, and the solubility and diffusion of this gas in the of these studies that ventilation may be a in other therapeutic such as exogenous and therapy directly to the lung while from This appears to have potential for a therapeutic in the of a variety of respiratory including surfactant or pulmonary and airway liquids are Because they are and of support gas can be from the a to pulmonary and function problems related to The of bromine atoms in as in perflubron can greater In the and can be used not only to lung but to PFC lung and and with are to the of the PFC during PLV a images both and with a in overall related to PFC by 30 minutes. studies of the lungs of animals and humans who CDH have to the of pulmonary hypoplasia and and of the PFC is a technique that to the of computed tomography and can allow of the of (Fig. small airway of the has been limited by of the at the of the PFC liquid perflubron as a agent has the of substantially more as small as liquids can be used for because hydrogen atoms are and the of the fluorine atom can be Because are of hydrogen is and body In addition, because oxygen dissolved in in the differences in oxygen tension can be by of the lung may be in monitoring gas exchange, and therapeutic fluorine to a the PFC liquid may a of in to studies by several have demonstrated the potential of LAV to support gas exchange and lung in the of pulmonary The basis of this application is related to low pressure alveolar recruitment and respiratory support that improved PLV studies of CDH in a supported from or after a of GV improved gas exchange and compared with animals supported with conventional GV. histology in animals that CDH and were with PLV was not improved to animals with the CDH with PFC at demonstrated improved function and histology compared with These that early and reduction of ventilatory pressures may reduce of the hypoplastic is that that lung may be by continuous intrapulmonary were for following and PFC of the to maintain up to The results demonstrated lung on increased weight total alveolar alveolar surface and alveolar compared with Because clinical investigational trials have been limited to a the lung was in with intrapulmonary PFC for after which the airway was and the animals were to spontaneous breathing 3 to of Although of PFC was to lung the gas airway and of all experimental animals were amounts of and These studies a potential for the use of PFC liquid as a mechanical for lung from several that administration of PFC liquids may reduce pulmonary and The of has been as a of function and In pulmonary as from levels in adult and immature was reduced during PLV compared with conventional GV This was with PFC doses as low as inspired gas and as early as 30 In other or from different and in to perflubron demonstrated to in studies of in the of perflubron that perflubron by as from combined levels in the with not the to which that the PFC to be present during for the to be same PFC been shown to and of human alveolar or of human that perflubron or effect on or following by In addition, concentrations of and from alveolar were not altered by from humans with PFC is from adult clinical trials with The capacity of from lavage of humans who was to that of blood In of adult humans who and were with or PLV, the blood and in the lavage were higher with than concentrations did not between and PLV, and levels were lower with liquids to and were to PFC, and following were to PFC with subsequent and did not of or to More the of perflubron not of the it be that perflubron not the ability of to to an during acute lung it appears that the of PFC may a mechanical or effect to reduce lung by and the effects of or on lung liquids have very high heat capacity to respiratory The pulmonary less in to than the In addition, because the lung surface is times that of the body surface the essentially in with the pulmonary and because the is lung is an heat a result of these and much more effective can the pulmonary administration of through breathing a by the is a potential to using LV techniques to and These heat exchange principles LV techniques have been demonstrated in both newborn and adult animals. of inspired liquid be in the It is that the support of this may to maintain temperature control in the human trials of PFC liquid breathing were in in and were in infants who severe respiratory failure. TLV was administered in two to by 15 of GV. A gravity-assisted was and tidal of liquid were to a lung for two The infants the and improvement in several including lung and gas was after LV was but the infants the used a of TLV, the of GV was after administration of PFC liquid to the immature lung. All of the infants in these studies from their respiratory but TLV was shown to support gas exchange and allow residual improvement in pulmonary function following return to GV. clinical trials were limited by the need for a liquid ventilator and breathing human have used a PLV to the years, several PLV studies using have been or are in and reported on preterm infants who severe in whom conventional treatment The infants were with PLV for up to hours by time on PLV for any was lungs were with to 20 and doses generally were administered The was not or The oxygen tension increased by the increased by and the oxygenation was reduced from a mean of to within of of It was that clinical improvement and in some infants who were not to and reported results for patients who CDH and were being for up to 5 on extracorporeal support PLV was in a for up to with This technique to be and was associated with improvement in gas exchange and pulmonary In a and infants who respiratory failure and were to improve while administered PLV with of for up to that the technique to be lung and lung volume in these initial studies of PLV in are and the of this technique in the who has severe and The of the to PLV is more than is in the preterm who has The preterm improvement in lung and gas exchange within hours of PLV most to in surface tension and volume lung function in the debris which over several studies have PLV in children, and has used a control reported on patients who requiring were with of PLV for 3 to improvement in gas exchange and pulmonary over and all patients and patients who requiring an improvement in gas exchange and pulmonary adverse related to the or technique when administering PLV for to up to years of who with PLV for up to of the patients who initial improvement in gas function did not of these studies that PLV may be and in the treatment of have been two PLV studies with in and adults who and were with of PLV for up to The reported a in the and an in pulmonary of the patients on their clinical experiences, they that PLV in this and may be associated with improvements in gas exchange and pulmonary In and a of PLV in adult patients who acute respiratory failure. patients for 5 and patients as and did not between the but was a significant improvement in in with PLV who were than years of The that PLV can be with in this and suggested that trials be with to of this a PLV adult with is in and It is to the effectiveness of PLV over in a Although the use of other for clinical trials is it is that PLV studies with in the neonatal and are on the results of this adult of initial trials have demonstrated the potential and of this in of but a of the of PLV the results of use of PFC liquids as an respiratory medium was on mechanical and to support pulmonary gas exchange and the years, the pulmonary application of PFC liquids has to their use as a to agents directly to the a to lung as a bronchopulmonary and as a potential medium to application of LV techniques remains the potential to treat lung disease with less of and to a means for of respiratory such as surfactant HFOV, and nearly patients in and have been in various clinical trials of PLV, and results are of PFC liquids with physicochemical will of LAV techniques for With the and of the of PFC LAV will an in clinical and clinical should the applications and of this therapeutic to respiratory