Version May 2024
INTRODUCTION — Liquid ventilation (LV) is an investigational technique of mechanical ventilation in which the lungs are insufflated with an oxygenated perfluorochemical liquid rather than an oxygen-containing gas mixture. Despite its theoretical advantages, efficacy studies have been disappointing and the optimal clinical use of LV has yet to be defined [1].
The technique and potential applications of LV will be reviewed here. Conventional and alternative modes of gas-phase mechanical ventilation are discussed separately. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Modes of mechanical ventilation".)
PROPERTIES — The ideal fluid for LV is nontoxic, has a low surface tension, is capable of dissolving large amounts of oxygen and carbon dioxide, has minimal systemic absorption, and is chemically stable [2]. Following work with hyperbaric saline ventilation [3], researchers demonstrated that perfluorochemicals (PFCs) had many of these properties and could be used as a medium for liquid breathing in rodents [4].
The use of perfluorochemicals, rather than nitrogen, as the inert carrier of oxygen and carbon dioxide offers a number of theoretical advantages for the treatment of acute lung injury, including:
●Reducing surface tension by maintaining a fluid interface with alveoli
●Opening of collapsed alveoli by hydraulic pressure with a lower risk of barotrauma
●Providing a reservoir in which oxygen and carbon dioxide can be exchanged with pulmonary capillary blood
●Functioning as a high efficiency heat exchanger
●Mobilizing alveolar and airway debris and exudates
Physical properties — PFCs are organic compounds in which some carbon-bound hydrogen atoms have been replaced with fluorine atoms [5]. Perflubron (LiquiVent), the only medical grade PFC available for use in human LV trials, consists of a long, linear-fluorinated hydrocarbon chain. Perflubron contains one bromide atom, making it radiopaque [5].
Hundreds of different PFC fluids with unique biomedical properties exist. The structure of several examples of these compounds is shown in the figure (figure 1). The table compares the physical properties of air, water, and saline with three PFCs that have been studied for LV (table 1) [6,7].
PFC fluids are clear, colorless, odorless, and inert. Oxygen, carbon dioxide, and other gases are highly soluble in these fluids; they can dissolve over 15 times the amount of oxygen per given volume as plasma [8]. PFCs are poor solvents for most other biological compounds.
PFCs are stable, insoluble in water, can be stored indefinitely at room temperature, and can be autoclaved [8,9]. In contrast to saline, PFCs do not wash out surfactant [1]. Almost all PFC fluids have low surface tension and are nonbiotransformable. However, PFCs have a high viscosity, which makes their flow characteristics problematic under certain circumstances.
Pharmacokinetics — Very small amounts of PFCs diffuse into the pulmonary capillary blood and dissolve in blood lipids [10]. The rate of uptake in the blood depends upon the PFC vapor pressure, permeability coefficients of the blood vessels, solubility of the particular PFC used, and the degree of ventilation/perfusion matching.
Absorbed PFCs are scavenged by macrophages. The main route of PFC elimination is through the lungs via volatilization [11,12]. To a smaller degree, the chemicals are eliminated through the skin by transpiration. Perflubron blood concentrations are low but measurable, and persist for at least eight days following administration of the last dose of perflubron [13].
TECHNIQUES — Two methods of perfluorochemical (PFC)-based LV have been used: total (tidal) LV and partial LV.
Total liquid ventilation — In total LV (TLV), the entire lung is filled with an oxygenated PFC liquid, and a liquid tidal volume of PFC is actively pumped into and out of the lungs. A specialized apparatus is required to deliver and remove the relatively dense, viscous PFC tidal volumes, and to extracorporeally oxygenate and remove carbon dioxide from the liquid [2,9,14].
TLV is initiated by insufflating the desired volume of pre-oxygenated PFC liquid (functional residual capacity plus tidal volume) into the lungs using a gravity-assisted device or more specialized equipment [6,9]. Optimum ventilation and oxygenation depend upon adequate minute ventilation coupled with sufficient time for diffusion of respiratory gases to and from the PFC liquid [6,9]. During the maintenance phase of TLV, a low respiratory rate (eg, four to six breaths per minute) is set with an inspiratory-to-expiratory (I:E) ratio of 1:2 to 1:3 [15]. At these respiratory rates and timing ratios, PFC fluid dwells in the lung long enough for diffusion of respiratory gases to occur, thus effecting pulmonary gas exchange. Tidal volumes and peak inspiratory and positive end expiratory pressures (PEEP) are adjusted based upon pulmonary mechanics and blood gases in the same manner as when gas ventilation is employed. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Positive end-expiratory pressure (PEEP)".)
TLV is weaned when sufficient clinical improvement has occurred such that gas ventilation will be adequate to support the patient; specific weaning parameters and techniques have not been fully evaluated. The return to gas ventilation is accomplished by a transition through a period of partial LV (see 'Partial liquid ventilation' below). PFC liquid is removed at the end of the expiratory phase, leaving a volume of PFC fluid equivalent to the functional residual capacity of the lung. Gas ventilation is begun, and the PFC fluid is not replaced or augmented as it is evaporated; elimination from the lung by evaporation generally requires one to seven days [6,16]. In some cases, small amounts of PFC are radiographically apparent in the lungs for several weeks or longer without apparent ill effects [16].
Partial liquid ventilation — In partial LV (PLV), the lungs are slowly filled with a volume of PFC equivalent or close to the FRC during gas ventilation. The PFC within the lungs is oxygenated and carbon dioxide is removed by means of gas breaths cycling in the lungs by a conventional gas ventilator [6].
PLV is initiated by insufflating PFC liquid (approximately 20 to 30 mL/kg) into the lungs using an intravenous syringe pump or by slowly pushing the fluid in over a 15-minute to one-hour period. The functional residual capacity is reached when a meniscus of PFC is present within the endotracheal tube at end-expiration [17].
As the fluid evaporates out of the lungs, it is intermittently and gradually replaced with additional PFC at approximately 2 to 8 mL/kg/hour to maintain a total liquid volume of functional residual capacity [6,9]. Typically, but not exclusively, pressure-controlled ventilation with the addition of PEEP is used to deliver gas ventilation, and fraction of inspired oxygen (FiO2) and PEEP are adjusted based upon pulmonary mechanics and blood gases [18].
Airway suctioning is still required with PLV [1]. PLV is discontinued by ceasing to replace the PFC that is lost through evaporation. Most of the intrapulmonary PFC evaporates in the next one to seven days, allowing a transition to gas ventilation [16].
Comparison — TLV allows the lavage and removal of lung secretions, meconium, or alveolar edema from the lower airways to a greater extent than PLV. In addition, the distribution of PFC within the lungs may be more uniform during TLV than PLV. However, TLV requires a specialized delivery apparatus, and increased airway resistance can make the tidal delivery of viscous PFCs difficult.
PLV provides some of the same benefits as TLV by maintaining a liquid interface in the alveoli, but does not require specialized equipment. The technique may also be possible in some patients in whom elevated airway resistance precludes the use of TLV. Periodic repositioning of the patient is required with both modes to ensure optimal distribution of PFC fluid within the lungs but is more important in PLV to maintain a liquid interface in as many alveoli as possible.
PHYSIOLOGIC OUTCOMES — LV offers a number of theoretical advantages over conventional gas ventilation, including better gas exchange and functional lung recovery by any of several mechanisms:
●Alveolar recruitment – Filling of alveoli with liquid rather than gas eliminates air-liquid interfaces and greatly reduces surface tension forces. Collapsed alveoli may also be recruited and stabilized by the hydraulic forces provided during LV. Alveolar expansion and stability is thus facilitated at much lower airway pressures, reducing the risk of barotrauma [14,19]. As more alveoli are filled with oxygen-rich perfluorochemical (PFC), the effective diffusing surface of the lung increases and is reflected by improvement in arterial oxygenation and compliance [20,21].
●Better V/Q matching – PFC fluids are denser than water and therefore deposit in dependent regions of the lungs. They improve ventilation/perfusion matching by facilitating gas exchange in lung units that were previously perfused but unventilated. The weight of PFCs within dependent lung zones also may redistribute pulmonary blood flow to nondependent zones that were previously ventilated but unperfused [22].
●Lavage – LV facilitates the removal of exudative material from the lung but does not interfere substantially with the production or function of surfactant [1,23]. During TLV, the cyclical removal and replacement of PFC liquid may cleanse the lungs while maintaining gas exchange [24]. During PLV, exudative material in the peripheral airways and alveoli is lavaged to the central airways for removal via suctioning [17].
●Anti-inflammatory effects – Some studies suggest reduced neutrophil and alveolar macrophage responses exist in the presence of PFCs, including attenuation of neutrophil adhesion, activation, and migration [25-31]. Preclinical studies suggest perfluorocarbons inhibit inflammatory cytokine expression and inflammatory mediator signaling pathways [32] and attenuate ICAM-1 expression in injured alveolar cells [33]. The removal of inflammatory cells and their mediators from the alveolar spaces may also provide benefit [26,34]. Finally, filling of the alveolus with PFCs may provide a mechanical barrier to intra-alveolar exudation and leukocyte and/or red blood cell translocation, with potential beneficial effects in reducing the intensity of inflammation and secondary lung injury.
●Temperature regulation – PFC liquids have a higher heat capacity than conventional gas mixtures. This allows the lung and pulmonary circulation to act as an internal heat exchanger [35]. PFC liquids can be used to warm the lungs and increase core body temperature or cool the lungs and decrease core body temperature, as required by clinical circumstances [6,36].
POTENTIAL INDICATIONS — The unique properties of perfluorochemical (PFC)-based LV make the technique potentially useful in a variety of neonatal and adult application. These applications remain investigational.
Neonatal applications
●Respiratory distress syndrome – Exogenous surfactant therapy in infants with neonatal respiratory distress syndrome (hyaline membrane disease) is limited by unequal delivery and distribution within the injured or premature lung [37]. LV may facilitate more uniform endogenous surfactant distribution, and may be of use in surfactant-unresponsive cases. In either event, LV can reduce surface tension, thereby reducing inflation pressure and barotrauma, and may stimulate surfactant synthesis [23,38].
●Meconium aspiration – Lavage associated with total LV (TLV) and partial LV (PLV) may remove meconium from the airways more effectively than conventional measures [39-41].
●Persistent pulmonary hypertension of the newborn – LV provides uniform delivery of oxygen to the distal regions of the lungs, potentially improving ventilation/perfusion matching and facilitating pulmonary vasodilation [6].
●Congenital diaphragmatic hernia – PLV may improve gas exchange more effectively than conventional gas ventilation in newborns with severe congenital diaphragmatic hernia and may provide mechanical stimuli (eg, pressure transduction) that favor neonatal lung growth [42-46].
●Temperature control – The heat exchange characteristic of PFCs may help maintain normothermia in premature infants with less reliance upon radiant warmers, which increase insensible water loss [6].
●Lung protection during cardiopulmonary bypass – Full, functional residual capacity dosing prior to bypass may reduce cardiopulmonary bypass-associated lung injury [47]. Anti-inflammatory effects, alveolar distention, oxygen-carrying capacity, and surfactant-like properties may protect the lung before and during cardiopulmonary bypass.
Adult applications
●Acute respiratory distress syndrome – LV potentially can improve gas exchange in ARDS by virtue of recruiting the atelectatic, consolidated, dependent regions of the lungs that contribute to the physiologic shunt observed during gas ventilation. Pulmonary blood flow is also redistributed to less severely injured and/or atelectatic regions of the lungs, thus improving ventilation/perfusion matching [14,21,22,48].
●Pneumonia – Lavage associated with TLV and PLV removes infectious and inflammatory debris from the airways [40,41]. Antibiotics such as gentamicin can be suspended within the PFC vehicle to potentially facilitate treatment or prevention of pneumonia [49].
●Cancer therapy – LV may augment the antineoplastic effects of radiotherapy and chemotherapy in the lung by inducing localized hyperthermia or hyperoxia of the lung surface. Concentrated, topical chemotherapeutic agents can also be delivered [5,8,50].
●Drug delivery – Mechanical abnormalities of the lung, intrapulmonary shunting, ventilation/perfusion mismatching, and elevated surface tension impede effective delivery of systemic and intratracheal drugs to the lungs during conventional gas ventilation [51]. Antibacterial perfluorocarbon ventilation (APV) may improve antibiotic delivery to the lungs [52]. Data from preliminary animal studies suggest that pulmonary uptake of antibiotics and ibuprofen and the efficacy of vasoactive drugs are better following intratracheal administration during LV than when administered intravenously [51,53-55]. In an animal model, administration of liquid perfluorocarbon containing emulsified tobramycin resulted in a higher local concentration and lower systemic concentration than conventional aerosolized tobramycin delivery [56]. New pulmonary drug delivery technologies such as lipid-based hollow-porous microparticles combined with perfluorocarbons are under investigation [57].
●Donor lung preservation – Because perfluorochemicals have both direct anti-inflammatory and alveolar stabilizing effects, these agents have been proposed as potential useful tools for organ preservation prior to lung transplantation. Preliminary investigations have suggested that LV results in decreased alveolar destruction when compared to standard (gas) ventilation [58,59]. (See "Lung transplantation: Donor lung procurement and preservation".)
●Therapeutic hypothermia – Preclinical studies of temperature management with perfluorocarbons delivered via partial or total LV and lung lavage suggest several potential clinical applications, including end-organ preservation post cardiac arrest [60].
CLINICAL OUTCOME — Clinical human data are limited and do not support routine use of total or partial LV at this time [16,39,40,42,61-69]. Most studies have evaluated the ability of LV to improve gas exchange and pulmonary function in animal models.
Trials that have compared PLV versus conventional mechanical ventilation (CMV) in adults with acute respiratory distress syndrome (ARDS) are listed below:
●A 2013 meta-analysis review of two randomized controlled trials that compared PLV with CMV in the treatment of acute lung injury with or without acute respiratory distress syndrome in adults evaluated two trials with a total of 401 participants [70]. There were nonsignificant trends towards a higher 28-day mortality and fewer ventilator-free days with PLV. Pooled estimates of adverse effects suggested an increased risk for bradycardia (p = 0.005) and increased though nonsignificant risks for hypoxemia, hypotension, barotrauma, and cardiac collapse.
•In one trial, 311 patients were randomly assigned to receive CMV, low dose PLV (lungs filled to the carina in the supine position), or high dose PLV (lungs filled to 5 cm caudal to the incisors in the supine position) [68]. There was no difference in mortality among the groups; however, patients who received PLV had fewer ventilator-free days and more adverse events.
•In a trial of 90 patients, those who received PLV were less likely to have progressive deterioration of gas exchange; however, there was no difference in the number of ventilator-free days, the incidence of mortality, or any respiratory parameter [66].
In a small trial that included 13 neonates with congenital diaphragmatic hernias on extracorporeal life support (ECLS), patients who received PLV had a nonstatistically significant improvement in survival and time on ECLS compared to patients who received CMV [67]. However, ventilator-free days were greater in the CMV group.
There are no published controlled studies of PLV versus other forms of ventilator management in the treatment of acute lung injury or ARDS in children (28 days to 18 years of age) [69].
ADVERSE EFFECTS — The complete range of toxicity due to perfluorochemicals (PFCs) is not known. Early studies using total LV (TLV) reported an increase in pulmonary vascular resistance with a decrease in cardiac index of approximately 40 percent, which resulted in lactic acidosis [1]. This probably was a consequence of lung overexpansion, which may decrease cardiac output and arterial blood pressure. In contrast, adverse direct hemodynamic effects appear uncommon during partial LV (PLV).
Other adverse effects observed during PFC LV include mucous plug formation, pneumothoraces, and bleeding complications, but it is unclear to what degree these relate to LV rather than the underlying disease [39,40].
The long-term adverse effects of breathing PFCs appear to be negligible but remain under investigation [9]. Perflubron may persist in extrapulmonary tissues for years following LV. Two case reports note the continued presence of perflubron in the mediastinum, the retroperitoneum, and the pleural space for 9 and 12 years, respectively [71,72]. Such case reports describe the presence of pseudocalcified extraparenchymal PFC nodules 9 to 15 years following LV [71-73]. Alveolar rupture may also allow PFC to leak into underaerated spaces.
LV potentially can complicate some of the supportive and general care that ventilated patients receive in the intensive care unit:
●PFC fluid is almost twice as dense as saline, and patient weights should not be followed as the sole index of fluid balance when LV is used [6,7]. A dry weight should be obtained before the start of LV, and patients should be weighed again immediately after the lungs are filled with PFC fluid.
●PFCs are radiopaque and will eliminate much of the diagnostic utility of chest radiography. All lung tissue will appear opacified during TLV; during PLV, an anterior-posterior supine film may appear uniformly radiopaque, but a lateral view of the chest will reveal the distribution of PFC primarily within the dependent portions of the lung. A chest radiograph should be obtained prior to and within an hour of filling the lung with PFC fluid.
●Heart sounds are more distinct during TLV than PLV. Breath sounds during PLV are notable for the presence of fine rales and coarse rhonchi. No audible breath sounds are present during TLV.
●The impact of LV upon the development of nosocomial pneumonia is uncertain. Lavaging the lung of infectious exudate during LV may be beneficial, but this may be offset by the loss of diagnostic information usually provided by chest radiography [6,24,39]. PFCs are thought to be inert.
●Use of LV is unpleasant for the patient, and therefore deep sedation and paralysis are necessary [6,14]. The principles of using sedative and paralytic agents are similar to those applied when conventional gas ventilation is employed. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal" and "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)
FUTURE — The future of LV is unclear. There are no current human LV trials, though basic science research using in vitro and animal lung models continues.
SUMMARY AND RECOMMENDATIONS
●Liquid ventilation (LV) is an investigational technique of mechanical ventilation in which the lungs are insufflated with oxygenated perfluorochemical (PFC) liquid rather than gas. (See 'Introduction' above.)
●PFC liquids are stable and nontoxic, with minimal systemic absorption. They dissolve large amounts of oxygen and carbon dioxide; thus, they are ideal for gas exchange. (See 'Properties' above.)
●Two techniques of PFC-based LV have been used, total (tidal) LV and partial LV. (See 'Techniques' above.)
●Theoretical advantages of LV over conventional gas ventilation include recruitment and stabilization of alveoli, improvement in V/Q matching, removal of exudative material from the lung, direct anti-inflammatory effects, and temperature regulation. (See 'Physiologic outcomes' above.)
●In theory, LV may be of benefit for numerous neonatal and adult diseases. Clinical trials, however, have shown little improvement in important clinical outcomes. As a result, LV cannot be recommended in routine clinical care. (See 'Potential indications' above and 'Clinical Outcome' above.)
●Adverse effects observed during LV include mucous plug formation, pneumothoraces, and bleeding complications, although it is unclear whether these were due to LV or the underlying disease. Long-term retention of PFC residue in nonparenchymal tissues has been reported. (See 'Adverse Effects' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karen J Tietze, PharmD, who contributed to earlier versions of this topic review.
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