ARTICLE Ventilation: Current Status Thomas H. Shaffer, PhD*, Marla R. Wolfson, PhD†, Jay S. Greenspan, MD‡ and cancer. For example, therapeutic OBJECTIVES treatment of 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 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 . 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 has ogy and the evolution of intensive (CMV). the potential to allow 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 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 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 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 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 ; 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 , 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 , 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 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 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 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 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 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. 2). nontoxic and biochemically inert. In Methods Because PFC liquids have a high addition, they are radiopaque. More heat capacity, the patient’s body than 100 different PFC liquids exist, TOTAL LIQUID VENTILATION temperature can be regulated easily although only a few commercially (TLV) and closely by the liquid tempera- available liquids meet both the phys- Several techniques have been inves- ture during ventilation. icochemical property requirements tigated for using PFC liquids as a Over the years, the liquid ventila- and purity specifications for respira- respiratory support medium. Early tor has been refined sufficiently to tory applications. work with PFC breathing in animals allow computer operation using the PFC liquids diffuse from the lung employed total immersion of several same control modes as gas ventila- into the circulation and are distrib- small animal species. In these exper- tors; that is, it is time-cycled and

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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 . 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 vol- FIGURE 2. A block diagram illustrating the system components and configuration of ume of PFC liquid less than or a double pump liquid . equal to the FRC while conventional GV is maintained (Fig. 3). It has can be pressure- or volume-limited, allows unique control and measure- been proposed that residual PFC is have the inspiratory-to-expiratory ment of FRC by monitoring the oxygenated and is time (I:E) ratio be changed, and change in weight as liquid is exchanged in the lung by means of have the waveform altered. Many of exchanged between the subject and the tidal gas movement provided by the same general principles used for the LV system. FRC and inspired GV. During PLV, the air-liquid gas ventilation are applied during oxygen concentration can be interface in the lungs is not elimi- LV. The ventilatory rate generally adjusted to optimize oxygenation. nated completely, so some of the remains constant at 5 breaths/min All manipulations can be made major mechanical advantages of a during TLV (due to longer diffusion within the boundaries of set pres- liquid-liquid interface may not be times of gases through liquids), and sure, volume, and flow limits. appreciated. However, this technique the tidal volume is used to regulate offers specific advantages over GV minute ventilation and, therefore, for many pulmonary disorders, par- PARTIAL LIQUID VENTILATION PaCO2. With a time-cycled system, ticularly where surfactant therapy is tidal volume is regulated by chang- (PLV) not an option. ing flow rates or pressure limits. Because initial TLV studies demon- A number of techniques have Unlike gas ventilation (GV), TLV strated residual improvements in been explored for LAV. Thus far, investigators have considered contin- uous 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 unoxy- genated 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 addi- tion of small amounts of PFC liquid (3 mL/kg) to high-frequency oscilla- tory ventilation (HFOV) resulted in a more rapid improvement in oxy- FIGURE 3. Illustration of PLV in a preterm . 1. The ventilator warms and genation for lung-injured piglets oxygenates PFC liquid during slow instillation. 2. As liquid enters the side port of the endotracheal tube, the ventilator carries PFC to the distal areas of the lung. compared with HFOV alone (piston- 3. As PFC liquid accumulates in the lungs, atelectatic regions of the lungs are driven). Although oxygenation expanded from A to B. 4. Oxygen and carbon dioxide are exchanged between improved over time in both groups alveolar PFC liquid and blood passing through the pulmonary capillaries. 5. Carbon with HFOV, increasing doses of dioxide is removed in expired gases by the ventilator. PFC did not result in any significant e136 NeoReviews December 1999 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 30, 2021 RESPIRATORY DISEASE Liquid Ventilation differences in oxygenation compared tional GV. The group prophylacti- on these findings, it was concluded with HFOV alone. Neither values cally treated with PFC liquid at that TLV improved pulmonary per- for PCO2 and pH nor cardiovascular delivery demonstrated improved fusion and ventilation-perfusion stability differed between groups. function compared with rescue matching. The combination of HFOV and treatment. small-dose PFC liquid may permit more effective oxygenation at lower ACUTE RESPIRATORY DISTRESS Nonrespiratory Applications mean airway pressures by facilitat- SYNDROME (ARDS) ing alveolar expansion and decreas- Term infants, pediatric patients, and DRUG DELIVERY ing intrapulmonary shunt. adults all can present with ARDS. Delivering drugs through the endo- Whether they are receiving or are tracheal tube is not a new concept candidates for ECMO, they often for intensive care clinicians; man- Respiratory Support have consolidated, collapsed lungs agement of pulmonary dysfunction Applications Using LAV with an aggressive inflammatory often includes delivery of biologi- process and extremely poor compli- cally active agents to the lung. The RESPIRATORY DISTRESS ance. Therefore, they potentially can physiologic properties of the lung as SYNDROME (RDS) be helped by lung recruitment and an exchanger for biologic agents Preterm infants characteristically improved compliance. Multiple labo- include its large surface area, thin have homogeneous surfactant defi- ratory studies have shown the ability walls, and accessibility to the entire ciency and immature parenchyma of LAV to improve gas exchange, cardiac output. Theoretically, insuf- and initially present with a purely mechanics, and cardiopulmonary flation of an agent directly to the restrictive lung disease that leads stability in both large animal models lung presents advantages for distri- quickly to atelectasis. The use of and neonatal animal models of bution and uptake. Over the years, surfactant replacement therapy and ARDS. this concept has led not only to prenatal steroids has substantially direct endotracheal drug delivery, improved the clinical course of these ASPIRATION SYNDROMES but to various methods for aerosol- infants, but they seem to have the Patients who have aspiration syn- ization of drugs during ventilation. most to gain from LAV, particularly dromes can benefit from the ability In the diseased lung supported with when applied early. Surface tension of PFC liquids to support pulmonary liquid, pulmonary blood flow is dis- forces are reduced or eliminated, mechanics and tributed more homogeneously and atelectasis is prevented or remedied, gas exchange and the liquid environment of the while lavaging developing fetal lung can be repro- the lung. PFC duced. The need for excessive venti- liquid has been lator pressures and inspired oxygen used to ventilate concentrations is diminished. Multi- lambs that have ple animal studies over the years meconium aspi- have demonstrated significant ration. In these improvements in pulmonary lambs, poor gas mechanics, gas exchange, and histol- exchange, acido- ogy in models of premature lung sis, and low pul- disease (Fig. 4). monary compli- ance were CONGENITAL DIAPHRAGMATIC present during HERNIA (CDH) GV; during sub- The newborn who has CDH faces sequent TLV, the dilemma of pulmonary hypopla- meconium was sia potentially complicated by sur- observed in the factant deficiency. PFC liquids have expired liquid. the potential to maximize recruit- Improvements ment of the hypoplastic lung while were noted dur- minimizing the surface tension ing TLV and forces related to surfactant defi- PLV in PaO2, ciency, thus allowing more efficient alveolar-arterial ventilation and minimization of (A-a) oxygen FIGURE 4. Changes in inspired oxygen tension (PiO2), Alveolar-arterial oxygen gradient (A-a DO ), arterial oxygen . Investigation of a lamb gradient, and 2 tension (PaO ), and carbon dioxide tension (PaCO ) during pulmonary com- 2 2 preparation of CDH supported with GV, followed by PFC LV, and recovery GV in preterm lambs. PLV, either prophylactically at birth pliance, and pul- Reprinted with permission from Shaffer TH, Douglas PR, or rescued after a period of GV, monary blood Lowe CA, Bhutani VK. The effects of liquid ventilation on showed improved gas exchange and flow was more cardiopulmonary function in preterm lambs. Pediatr Res. compliance compared with conven- uniform. Based 1983;17:303–306.

NeoReviews December 1999 e137 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 30, 2021 RESPIRATORY DISEASE Liquid Ventilation ventilation/perfusion is matched found to induce anesthesia effec- RADIOGRAPHIC IMAGING more evenly. Gas exchange can be tively in experimental animals while PFC liquids are useful contrast supported during pulmonary drug supporting cardiopulmonary media. Because they are inert, non- delivery in the liquid-filled lung, and function. biotransformable, and of varying the nonbiotransformable liquid pre- Inspired gases also lend them- radiopacity; support gas exchange; cludes any interaction between the selves well to this type of drug and can be vaporized from the lung, agent being delivered and the vehi- administration. Recent studies have they provide a useful diagnostic cle by which it is delivered. demonstrated physiologic responses imaging adjunct to evaluate pulmo- Several studies using LAV in to inspired nitric oxide (NO) during nary structure and function without preterm lambs that had RDS, PLV. The ability to deliver NO dur- intrinsic problems related to existing healthy and lung-injured term lambs, ing PLV probably is related to contrast agents. The presence of bro- and healthy rabbits have demon- recruitment of lung volume, distribu- mine atoms in PFCs, as in per- strated the feasibility of using LV tion of NO in the gas-ventilated flubron (LiquiVentTM), can confer techniques to deliver aqueous and regions of the lung, and the solubil- relatively greater radiopacity (Fig. lipid-soluble pharmacologic agents ity and diffusion of this gas in the 6). In the PFC-filled lung, conven- to the lung, including vasoactive PFC. tional radiography and HRCT can agents, , anesthetics, and Results of these studies suggest be used not only to illustrate lung vectors for gene transfer. Because that PFC-assisted ventilation may be structures, but also to evaluate PFC aqueous solutions are not readily a useful adjunct in delivering other lung distribution and sequential soluble in PFC liquids, the success therapeutic agents, such as broncho- elimination qualitatively and quanti- of this approach for homogenous dilators, exogenous surfactant, anti- tatively. Anteroposterior radiographs distribution and physiologic impact biotics, steroids, chemotherapeutics, with cross-table lateral views are has relied primarily on bulk flow required to evaluate the distribution mucolytics, antioxidants, and gene and turbulent mixing during TLV. pattern of the PFC during PLV qual- therapy products, directly to the lung A newly developed nanocrystal itatively. Whereas plain films indi- technology affords the opportunity while protecting nontargeted organs cate a predominate central clearance to increase the relative solubility of from iatrogenic pharmacologic pattern, sequential HRCT images agents by suspension in a PFC liq- effects. This approach appears to identify both central and peripheral uid (Fig. 5). This approach has been have vast potential for a therapeutic clearance, with a calculated 45% shown to yield therapeutic serum role in the management of a variety decrease in overall density related to levels and higher and more homoge- of respiratory problems, including PFC clearance by 30 minutes. nous pulmonary concentrations of surfactant deficiency, consolidation, Radiographic studies of the gentamicin in healthy and lung- exudative processes, malignancy, perflubron-filled lungs of animals injured neonatal animals than intra- persistent or acquired pulmonary and humans who had CDH have venous delivery when delivered hypertension, pneumonia, and air- proven informative to delineate either within the initial dose of PFC way reactivity. qualitatively the degree of pulmo- or sometime during PLV. In addi- tion to the previously mentioned biologic agents, halothane has been delivered in PFC liquid and was

FIGURE 5. A computer-generated molecular model of a PFC/gentamicin nanocrystal suspension. The white molecules represent gentamicin and the FIGURE 6. Conventional chest radiograph of a patient receiving ECMO with red molecules represent the PFC perflubron in the lungs. Perflubron is distributed uniformly in the lungs and imparts perflubron. high radiopacity. e138 NeoReviews December 1999 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 30, 2021 RESPIRATORY DISEASE Liquid Ventilation nary hypoplasia and distribution and oxygen dissolved in PFCs affects T1 space fraction, and normal alveolar elimination patterns of the PFC in the NMR signal, regional differ- numerical density compared with liquid. ences in oxygen tension can be controls. Because clinical investiga- Virtual bronchoscopy is a rela- mapped by assessing calibrated spin- tional trials have been limited to a tively new technique that adds post- lattice relaxation times. NMR imag- 7-day exposure, the lung growth processing software to the three- ing of the PFC-filled lung may be study was repeated in lambs with dimensional presentations of helical clinically useful in monitoring intrapulmonary PFC distension for computed tomography and can allow regional gas exchange, organ func- 7 days after which the airway cathe- four-dimensional imaging of the tion, biochemical mechanisms, and ter was removed and the animals inside of hollow viscera (Fig. 7). therapeutic measures. Finally, were recovered to spontaneous Evaluating small airway pathology because corresponds to a breathing until 3 to 6 months of age. of the tracheobronchial tree has been proton image, the PFC liquid may Although 7 days of PFC distension limited by poor resolution of the provide a way of assessing was insufficient to promote lung bronchioles at the secondary lobule ventilation-perfusion functions in growth, the gas exchange, ventila- level. Use of the PFC liquid per- relationship to anatomic structure. tion/perfusion scans, airway epithe- flubron as a bronchographic contrast lium, and alveoli of all experimental agent has enhanced markedly the animals were normal despite vari- navigation of substantially more dis- LUNG EXPANSION AND GROWTH able amounts of intrapleural and tal airways as small as 0.8 mm. OF THE HYPOPLASTIC LUNG interstitial PFC. These studies sug- PFC liquids can be used for Recent studies by several laborato- gest a strong potential for the use of nuclear magnetic resonance (NMR) ries have demonstrated the potential PFC liquid as a mechanical stimulus imaging because hydrogen atoms are of LAV to support gas exchange for lung growth without pathophysi- absent and the NMR spectra of the and lung mechanics in the presence ologic consequences. 19F natural fluorine atom can be of pulmonary hypoplasia. The basis measured. Because PFCs are devoid of this application is related to low of hydrogen atoms, no magnetic pressure alveolar recruitment and CELLULAR EFFECTS resonance imaging signal is pro- respiratory support that facilitates Growing evidence from several lab- duced, and PFC-filled body cavities improved ventilation-to-perfusion oratories suggests that intratracheal appear dark. In addition, because matching. PLV studies of CDH in a administration of PFC liquids may lamb preparation supported either reduce pulmonary and from birth or rescued after a period injury. The mechanism of action has of GV showed improved gas been speculated as a direct modifi- exchange and compliance compared cation of cell function and chemo- with animals supported with conven- taxis. In one study, pulmonary neu- tional GV. Lung histology in ani- trophil infiltration, as assessed from mals that had CDH and were res- myeloperoxidase levels in adult cued with PLV was not improved injured and immature lungs, was relative to animals treated with reduced during PLV compared with CMV, although the CDH lamb prep- conventional GV support. This aration prophylactically treated with response was observed with PFC PFC at delivery demonstrated doses as low as PFC-saturated improved function and histology inspired gas and as early as 30 min- compared with rescue treatment. utes posttreatment. In other studies, These data suggest that early inter- alveolar or circulating macrophages vention and reduction of ventilatory obtained from different species, pressures may reduce barotrauma of including humans, and exposed in the hypoplastic lung. vitro to perflubron demonstrated Exciting evidence is accumulating decreased responsiveness to potent that suggests that lung growth may stimuli. Recent in vitro studies of be accelerated postnatally by contin- Escherichia coli lipopolysaccharide uous PFC-based intrapulmonary dis- (LPS)-stimulated macrophages in the tension. Neonatal lambs were stud- presence of perflubron showed that ied for 21 days following isolation perflubron decreased NO production and PFC distension of the right by approximately 50%, as assessed upper lobe to maintain up to 10 mm indirectly from combined nitrite/ Hg intrabronchial pressure. The nitrate levels in the cell media. Pre- results demonstrated accelerated treatment with perflubron, however, FIGURE 7. Virtual bronchoscopic image lung growth based on increased did not alter the LPS-stimulated of the airway (4 cm proximal to the right upper lobe volume-to-body macrophages to elevate NO end carina). Top image: without the weight ratio, total alveolar number, products, which indicates that the instillation of PFC. Bottom image: with total alveolar surface area, normal PFC had to be present during stimu- PFC instillation in the lungs. histologic appearance, normal air- lation for the response to be blunted.

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This same PFC liquid, perflubron, TEMPERATURE CONTROL liquid to the immature injured lung. has been shown to decrease cytokine PFC liquids have very high heat All of the infants in these studies production (tumor necrosis factor capacity relative to respiratory gases. ultimately died from their underly- [TNF] alpha, interleukin [IL] 1, IL The pulmonary vasculature vasocon- ing respiratory disease, but TLV was 6, IL 8) and chemotaxis of activated stricts less in response to hypother- shown to support gas exchange and human alveolar or circulating mac- mia than does the skin vasculature. allow residual improvement in pul- rophages. One study of human cir- In addition, because the lung surface monary function following return to culating macrophages indicated that area is large (35 times that of the GV. Further clinical trials were lim- perflubron had little or no effect on body surface area), the entire cardiac ited by the need for a medically leukotriene, chemotaxis, or superox- output essentially comes in contact approved and ide anion release following activa- with the pulmonary surface, and medical-grade breathing fluid. Sub- tion by LPS, TNF-alpha, and because the epithelial barrier is thin, sequent human protocols have used -formyl-Met Leu-Phe stimulation. In the lung is an excellent heat a PLV approach to LV. addition, basal concentrations of exchanger. As a result of these ana- Over the past 6 years, several TNA-alpha, IL 1, and IL 6 from tomic and physiologic factors, much PLV studies using sterile perflubron TM unstimulated alveolar macrophages more effective warming/cooling can (LiquiVent ) have been completed were not altered by perflubron. occur via the pulmonary administra- or are ongoing in humans. Leach Data from humans treated with tion of heat/cold (especially through and collaborators reported on 13 intratracheal PFC is emerging from breathing a heated/cooled liquid) preterm infants who had severe RDS ongoing adult clinical trials with than by warming/cooling the skin. in whom conventional treatment had PLV. The oxidant-generating capac- Hence, there is a potential benefit to failed. The infants were treated with ity of neutrophils obtained from using LV techniques to provide PLV for up to 96 hours by protocol of PFC- hyper- and hypothermia. These heat (maximal time on PLV for any treated humans who had ARDS was exchange principles employing LV infant was 76 h). Their lungs were TM similar to that of peripheral blood techniques have been demonstrated filled with LiquiVent to approxi- neutrophils. In another study of experimentally in both newborn and mately 20 mL/kg, and supplemental adult humans who had ARDS and adult animals. Temperatures of doses generally were administered were treated with either CMV or inspired liquid must be controlled hourly. The study was not random- PLV, the white blood cell count, carefully in the normothermic ized or blinded. The arterial oxygen neutrophils, protein, IL 1, and IL 6 patient. It is noteworthy that the tension increased by 138%, the in the bronchoalveolar lavage were adjunctive support of this media dynamic compliance increased by higher with CMV than PLV; IL 8 may help to maintain temperature 61%, and the oxygenation index was concentrations did not differ control in the thermally unstable reduced from a mean of 49 to 17 between CMV and PLV, and IL 10 neonate. within 1 hour of initiation of PLV. levels were lower with PLV. It was concluded that clinical PFC liquids also appear to affect improvement and survival occurred neutrophil-epithelial cell interactions. in some infants who were not pre- When neutrophils and epithelial Clinical Studies dicted to survive. cells were exposed simultaneously Pranikoff and associates reported to PFC, adhesion and target cell NEONATAL results for four patients who had injury following stimulation were The first human trials of PFC liquid CDH and were being managed for reduced. Prior exposure to PFC with breathing were conducted in Phila- up to 5 days on extracorporeal life subsequent washing and stimulation delphia, Pennsylvania in 1989 and support (ECLS). PLV was per- did not alter neutrophil release of were initiated in near-death infants formed in a phase I/II trial for up to proinflammatory stimuli or adhesion who had severe respiratory failure. 6 days with daily dosing. This tech- to epithelial cells. More importantly, TLV was administered in two 3- to nique appeared to be safe and possi- because the presence of perflubron 5-minute cycles separated by bly was associated with improve- does not cause direct suppression of 15 minutes of GV. A gravity- ment in gas exchange and the neutrophil response system, it assisted approach was used, and pulmonary compliance. In a similar would be expected that perflubron tidal volumes of liquid were given study, Greenspan and coworkers would not impede the ability of neu- to a liquid-filled lung for two treated six term infants who had trophils to respond to an inflamma- sequential 5-minute cycles. The respiratory failure and were failing tory challenge during acute lung infants tolerated the procedure and to improve while receiving ECLS. injury. showed improvement in several They administered PLV with hourly In summary, it appears that the physiologic parameters, including dosing of LiquiVentTM for up to presence of PFC may provide a lung compliance and gas exchange. 96 hours. They concluded that the mechanical barrier or direct cytopro- Improvement was sustained after LV technique appeared to be safe, tective effect to reduce lung injury was discontinuated, but the infants improved lung function, and by attenuating leukocyte infiltration eventually deteriorated. Hence, recruited lung volume in these and the effects of local or circulat- although the protocol used a form of infants. ing proinflammatory mediators on TLV, the benefit of GV was sus- These initial studies of PLV in lung structures. tained after administration of PFC neonates are encouraging and sug- e140 NeoReviews December 1999 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 30, 2021 RESPIRATORY DISEASE Liquid Ventilation gest the feasibility of this technique observed improvements in gas complementing existing forms of in the neonate who has severe RDS exchange and pulmonary compli- respiratory management such as sur- and ARDS. The response of the sick ance. In another study, Bartlett and factant therapy, ECMO, HFOV, and term infant to PLV frequently is others presented a phase II random- inhaled NO. To date, nearly 500 more gradual than typically is ized, controlled trial of PLV in patients in hospitals across North observed in the preterm infant who 65 adult patients who had acute America and Europe have been has RDS. The preterm infant often hypoxemic respiratory failure. Forty enrolled in various clinical trials of experiences improvement in lung patients received LiquiVentTM for PLV, and preliminary results are compliance and gas exchange within 5 days, and 25 patients served as encouraging. hours of PLV initiation, most likely controls. Ventilator-free days and The future availability of addi- due to reductions in surface tension mortality did not differ between the tional biomedical-grade PFC liquids and volume recruitment. Improving groups, but there was a statistically with varying physicochemical char- lung function in the term infant significant improvement in acteristics will enable further tailor- often requires debris removal, which ventilator-free days in subjects ing of LAV techniques for individ- occurs gradually over several days. treated with PLV who were younger ual applications. With continued than 55 years of age. The authors efforts toward establishing the effi- PEDIATRIC concluded that PLV can be accom- cacy and safety of the biologic inter- plished with safety in this popula- action of PFC fluids, LAV undoubt- Three studies have evaluated PLV in tion and suggested that larger trials edly will assume an integral role in children, and none has used a con- be initiated with special consider- clinical medicine. Continued labora- trol group. Gauger et al reported on ation to age stratification. tory and clinical research should six pediatrics patients who had As of this writing, a 480-patient, define further the applications and ARDS requiring ECLS. Children phase III, PLV adult trial with limitations of this alternative thera- were treated with daily dosing of LiquiVentTM is ongoing in North peutic approach to respiratory LiquiVentTM PLV for 3 to 7 days. America and Europe. It is designed management. Some improvement in gas exchange to distinguish the effectiveness of and pulmonary compliance occurred PLV over CMV in a clearly defined over time, and all patients survived. ARDS population. Although the use Similarly, Hirschl and coworkers SUGGESTED READING of other PFCs for clinical trials is treated seven pediatric patients who Bartlett R, Croce M, Hirschl RB, et al. A emerging, it is noteworthy that PLV had ARDS requiring ECLS. They phase II randomized, controlled trial of studies with LiquiVentTM in the partial liquid ventilation (PLV) in adult found an improvement in gas neonatal and pediatric population are patients with acute hypoxemic respiratory exchange and pulmonary compliance currently on hold awaiting the failure (AHRF). Crit Care Med. 1997;25: without adverse events related to the A135 results of this pivotal adult trial. drug or technique when administer- Cox C, Wolfson MR, Shaffer TH. Liquid Results of initial phase I/II trials ventilation: a comprehensive overview. ing PLV for 1 to 7 days. Finally, have demonstrated the potential Neonatal Network. 1996;15:31–43 Toro-Figueroa et al treated 10 chil- safety and efficacy of this therapy, Day SE, Gedeit RG. Liquid ventilation. Clin dren up to 17 years of age who had Perinatol. 1998;25:711–732 particularly in younger populations ARDS with PLV for up to 96 hours. 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Pediatrics. 1997;99:E2 To date, there have been two phase monary gas exchange and function. Hirschl RB. Liquid ventilation in the setting I/II PLV studies with LiquiVentTM Over the years, the pulmonary appli- of respiratory failure. ASAIO Journal. 1998;44:231–233 reported in adults. Hirschl and col- cation of PFC liquids has evolved to Hirschl RB, Pranikoff T, Wise C, et al. Initial leagues treated 10 adults who had include their use as a vehicle to experience with partial liquid ventilation in ARDS and were receiving ECLS deliver agents directly to the lung, adult patients with acute respiratory dis- with daily dosing of PLV for up to as a substance to facilitate lung tress syndrome. JAMA. 1996;275:383–389 7 days. The authors reported a growth, as a bronchopulmonary con- Jacobs HC, Mercurio MR. Perfluorocarbons in the treatment of respiratory distress syn- decrease in the physiologic shunt trast agent, and as a potential cyto- drome. 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