Liquid ventilation

Abstract

Human have lungs to breathe air and they have no gills to breath liquids like fish. When the surface tension at the air-liquid interface of the lung increases as in acute lung injury, scientists started to think about filling the lung with fluid instead of air to reduce the surface tension and facilitate ventilation. Liquid ventilation (LV) is a technique of mechanical ventilation in which the lungs are insufflated with an oxygenated perfluorochemical liquid rather than an oxygen-containing gas mixture. The use of perfluorochemicals, rather than nitrogen as the inert carrier of oxygen and carbon dioxide offers a number of advantages for the treatment of acute lung injury. In addition, there are non-respiratory applications with expanding potential including pulmonary drug delivery and radiographic imaging. It is well-known that respiratory diseases are one of the most common causes of morbidity and mortality in intensive care unit. During the past few years several new modalities of treatment have been introduced. One of them and probably the most fascinating, is of LV. Partial LV, on which much of the existing research has concentrated, requires partial filling of lungs with perfluorocarbons (PFC's) and ventilation with gas tidal volumes using conventional mechanical ventilators. Various physico-chemical properties of PFC's make them the ideal media. It results in a dramatic improvement in lung compliance and oxygenation and decline in mean airway pressure and oxygen requirements. No long-term side-effect reported.

HISTORICAL BACKGROUND

The use of fluids such as saline, silicone oil sand perfluorocarbons (PFC's) for breathing has been under investigation for many decades. The potential use of liquid ventilation (LV) has been investigated since 1962 when Kylstra evaluated the ability to sustain gas exchange in mice spontaneously breathing saline oxygenated at 6 atmospheres. In 1966, Clark and Gollan subsequently demonstrated that spontaneously breathing mice could survive when submerged in PFC under normobaric conditions.

These investigators observed that mice, rats and other animals could survive in complete immersion in oxygen-saturated silicon oils for prolonged periods of time and recover uneventfully. Silicone oils found to be toxic and hence only PFCs remained for possible use.[1]

PFCs were synthesized during the development of the atomic bomb (The Manhattan Project) where they were given the code name “Joe's stuff.”[2] Over the last 40 years, LV has been studied in various animal models: normal, premature and with lung injury.[1,2,3] The first trial of LV in preterm neonates in 1989 showed the feasibility and potential of LV in humans.[4] Much of the work in the 1990's has focused on fine tuning the technique to complement clinical trials and elaborately exploring potential toxicity and interactions with other organ systems.

ABOUT PFC’S

The PFC liquids used to support pulmonary gas exchange are a type of synthetic liquid fluorinated hydrocarbon (hydrocarbons with the hydrogen replaced by fluorine and for perflubron where a bromine atom is added as well)[2] with high solubility for oxygen and carbon dioxide. These are chemically and biologically inert, clear and odorless, have low surface tension and it is not metabolized in kidney or liver. The oxygen carrying capacity can be more than 3 times that of blood (35-70 ml gas/dl at 25°C) and that of CO2 is approximately four times greater than that for oxygen (122-255 ml/dl).[5] They can be stored at room temperature. In general, because PFC liquids are more dense and viscous than gas, with slower spreading and higher diffusion coefficients, assisted mechanical ventilation techniques are required to support pulmonary gas exchange when the lung is totally or partially filled with this medium. They get uniformly distributed within the lung and recruit atelectatic alveoli, which are maintained by low surface tension. The low surface tension (14-18 dyne/cm) and high density (1.7-1.9 mg/ml) allows PFC to serve as “surfactant substitutes8.” Replacement of the gas functional residual capacity (FRC) by PFC liquid eliminates the alveolar-membrane air-liquid interface. There is a lavage effect during liquid breathing that mobilizes alveolar and bronchiolar exudate and fluid to the central airways, where they can be removed by suctioning. Perflubron has a positive “spreading coefficient.” This physical chemistry property is meaningful in drug distribution and means that perflubron tends to spread rapidly and homogeneously to the entire lung. It efficiently migrates to the most dependent portion of the lung, where aqueous fluid and debris tend to consolidate and where gas exchange is most severely disrupted. Each of these attributes makes this chemical an effective ventilation medium and allows effective gas exchange through the PFC filled lungs. PFC has been shown to provide mechanical protection to the developing and/or injured adult lung by reducing surface tension and reducing pressure requirements along with a cytoprotective effect by providing a mechanical barrier at plasma membranes and by attenuating leukocyte infiltration 9.

The most current studies report PFC levels of less than 5.8 mcg/ml of blood. In tissue, the lowest levels were found in the liver and the highest levels in the lung, followed by fat. Excluding lung and fat, tissue levels were less than 250 mg/g of tissue after 24 h of LV.[6]

Non-medical uses of PFC include the cosmetic industry for their water retention properties as cooling agents and as insulators. In medical applications, besides use as a respiratory medium, PFCs are being evaluated as contrast agents for computerized tomography and magnetic resonance imaging (MRI), as sensitizing agents during radiotherapy and as possible intravenous oxygen-carrying agents.[2,7]

PERSPECTIVE AND REVIEW

The two main types of LV delivery techniques are total (or tidal) liquid ventilation (TLV) and partial liquid ventilation (PLV) sometimes called (PFC associated gas exchange).

TLV

The lungs are filled with PFC to a volume equivalent to the FRC, approximately 30 ml/kg and a “liquid ventilator” is used to generate tidal breathing with PFC. Optimal CO2 clearance is achieved when ventilation is performed at a rate of 4-5 breaths/min. Typical tidal volumes are in the 15-20 ml/kg range. One of the advantages of TLV is that exudates may be lavages from the airways in the setting of respiratory failure. In addition, the distribution of PFC within the lungs may be more uniform during TLV.[3] Practically, this method was not proved to be adequate for prolonged ventilation.[8]

PLV

PLV is a modified approach in which PFC liquid is instilled into the lungs during continuous positive pressure gas ventilation, sparing the ventilatory circuit. The liquid-filled lungs are ventilated with the use of tidal breaths of gas delivered by a standard positive pressure gas ventilator 10. Much of the existing research has concentrated on PLV. Several studies of PLV utilizing the PFC sterile perflubron (C8F17Br1, Liqui Vent;

Alliance Pharmaceutical Corporation, San Diego, California) have been completed or are ongoing in humans.[9,10]

Technique

The Liqui Vent dose packaging is designed for hanging on IV pole at the bedside of the mechanically ventilated patient, where it is drip-infused through the Liqui Vent administration set, a sterile-wrapped infusion set that connects to the standard side port adapter fitting on the patient's endotracheal tube and provides the physician with drip-rate and dose-volume control. Other PFC's, which have been studied, include FX-80, FC-75, FC-43 (perfluorotributylamine) and perfluorooctane. Perflubron is instilled at a rate of 1 ml/kg body weight/min through the side port of endotracheal tube without interrupting mechanical gas ventilation, maintaining a positive end expiratory pressure of 4 cm of water, until a column of fluid welled up in the endotracheal tube during momentary disconnection from the ventilator. The volume of perflubron required to produce this meniscus represents the infant's FRC. A typical initial dose of PFC during PLV is equivalent to FRC (~30 ml/kg) 9. The optimum PFC filling strategy and subsequent gas ventilation scheme is still under investigation. Schemes that have been explored include (1) brief periods (35 min) of TLV (2) rapid instillation of a bolus (upto 30 ml/kg) of oxygenated PFC with the ventilator disconnected and (3) slow infusion during continuous gas ventilation13. Ventilator settings or the rate of instillation of perflubron are adjusted to reflect the changing lung mechanics. Perflubron is added as needed to replace liquid lost through evaporation and to maintain the liquid FRC throughout the treatment period. The rate of supplemental administration of perflubron reflects a loss or gain of FRC. As a further refinement of the technique, in order to both quantify and replace evaporative losses, selective adsorption of the exhaled PFC can be done using adsorbent silicon-rich zeolith (organophil and hydrophob).

Classification of clinical applications of LV

1. Classification for LV comprises of severe respiratory failure due to; (a) Hyaline membrane disease (HMD), (b) Adult respiratory distress syndrome, (c) Meconium aspiration syndrome (MAS), (d) Pulmonary interstitial emphysema and (e) Congenital diaphragmatic hernia (CDH)

2. Future applications (experiments done on animals) for LV include; pulmonary contusion, Inhalation syndrome, cystic fibrosis, pulmonary alveolar proteinosis, drug delivery, radiographic imaging, temperature control, cellular effect, growth of the hypoplastic lung, lung protection during cardiopulmonary bypass, lung protection during organ donation and cancer therapy.

Human neonatal applications

Complications of prematurity are still common despite advances in perinatal care of preterm infants.[11] The use of surfactant replacement therapy and prenatal steroids has substantially improved the clinical course of some preterm infants, but not all of them respond[6] If new conventional ventilatory interventions fail, extracorporeal membrane oxygenation is the only alternative method, but is a complex, invasive and costly technique and difficult to apply to small infants. PFC LV is started as a new promising technique to solve ventilation problems associated with prematurity.[11]

The first human trials of PFC liquid breathing were conducted in Philadelphia, Pennsylvania in 1989 and were initiated in near-death infants who had severe respiratory failure. TLV was administered and a gravity-assisted approach was used. The infants tolerated the procedure and showed improvement in several physiologic parameters, including lung compliance and gas exchange. Improvement was sustained after LV was discontinued, but the infants eventually deteriorated. All the infants in these studies ultimately died from their underlying respiratory disease.[3,6]

Besides quantification of a continuous substitution the possibility to recuperate PFC arises.[12] Leach et al.,[8] reported a multi-centric study on 13 premature infants with gestational age ranging from 24 to 34 weeks (mean 28 weeks), birth weight ranging from 640 to 2000 g (mean 1055 g), with severe respiratory distress syndrome (RDS) on whom conventional treatment, including multiple surfactant therapy had failed. PLV was initiated for about 76 h. The primary end points were safety (assessed on the basis of heart rate, blood pressure, chest films, cranial ultrasonographic studies and clinical laboratory values) the presence or absence of new medical conditions and development progress. Secondary end points included changes in arterial oxygen tension, arterial carbon dioxide tension, dynamic compliance, ventilatory requirements and oxygenation index and survival. Within 1 h after instillation of PFC, the arterial oxygen tension increased by 138% and oxygenation index reduced from 49 ± 60 to 17 ± 16. The dynamic compliance increased during the 1^st h by more than 60% (from 0.18 ± 0.12 ml/cm of water/kg during gas ventilation to 0.29 ± 0.12 ml/cm of water/kg during PLV). Some of the adverse events noted during PLV included: endotracheal tube obstruction (this material was viscous, tenacious and greater in amount than present during the gas ventilation and could be removed by suctioning with saline), transient hypoxemic episodes, which were related to drug dosing and pneumothorax. Most of these events were not considered to be related to the experimental therapy. Eight of the 13 infants survived and neurodevelopmental follow-up at 4 months of age showed normal hearing and vision with mental and psychomotor development appropriate for the adjusted age. None of the infants had cerebral palsy. According to the authors, PLV not only improved the clinical condition, but also achieved survival of some infants who might have died without this therapy. Pranikoff and associates reported results for four patients who had CDH and were being managed for up to 5 days on extracorporeal life support (ECLS). PLV was performed for up to 6 days with daily dosing. Improvement was noticed in gas exchange and pulmonary compliance.[9]

Leach et al.[8] treated six term infants who failed to improve while receiving ECLS, with PLV 190 using perflubron for up to 96 h. The study concluded that the technique appears to be safe, to improve lung function and to recruit lung volume in these infants. These results show that PLV can be performed safely in critically ill-infants with severe RDS. The positive end expiratory pressure exerted by the liquid stabilizes the alveolar architecture so that alveoli are recruited and the FRC increases.[13]

The improved compliance permits ventilation with increased tidal volumes, resulting in increased gas exchange and the redistribution of blood flow in lungs filled with PFC liquid may contribute to improved ventilation-perfusion mismatching. Overall, process of switching from liquid to gas ventilation was uncomplicated with sustained improvement in gas exchange.

We now understand some of the mechanisms by which ventilation/perfusion mismatching is improved during PLV in the setting of respiratory failure. The pre-term infant often experiences improvement in lung compliance and gas exchange within hours of PLV initiation that is most likely due to reduction in surface tension and alveolar volume recruitment.[4] The response in a term infant to PLV appears to be more gradual than is generally observed in the pre-term infant with RDS and often requires removal of debris.[14]

Application on human adults

Hirschl et al. treated 10 adults who had acute respiratory distress syndrome (ARDS) and reported a decrease in the physiologic shunt and an increase in pulmonary compliance; 50% of the patients survived in their study. Based on their clinical experiences, they concluded that PLV may be associated with observed improvements in gas exchange and pulmonary compliance.[15]

Bartlett and others presented randomized, controlled trial of PLV in 65 adult patients who had acute hypoxemic respiratory failure. Forty patients received PLV for 5 days and 25 patients served as controls. Ventilator-free days and mortality did not differ between the groups, but there was a statistically significant improvement in ventilator-free days in subjects treated with PLV who were younger than 55 years of age.[16]

In another larger trial, 311 patients were randomly assigned to receive 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). There was no difference in mortality among the groups; however, patients who received PLV had fewer ventilator-free days and more adverse events including pneumothorax, hypoxic episodes and hypotensive episodes.[17] The mechanical lavage associated with TLV may have a salutary effect in the setting of ARDS pneumonia or MAS since exudate may be evacuated from the lungs. Specifically, the atelectatic, consolidated, dependent regions of the lungs, which contribute greatly to associated physiologic shunt observed during gas ventilation in the setting of ARDS, are reinflated during LV. A second effect of the relatively dense PFC may be to redistribute blood flow from the dependent to the non-dependent regions of the lung.[18] In doing so pulmonary blood flow may be redistributed to less severely injured/atelectatic areas of the lungs with associated improvement in ventilation/perfusion matching. After PLV, there is an increase in total amount of alveolar surfactant, improved quality of the secreted surfactant and an attenuation of surfactant inhibition by removing inhibitory substances typically present at the alveolar level during respiratory failure. PLV is a recruitment strategy as it splits open collapsed alveoli and keeps them in that state while it can also be labeled as a lung protective strategy as it diminishes the need for high FiO₂ and airway pressures.[12] The chest roentgenogram has been used to qualitatively assess the amount of drug and its distribution. Perflubron symmetrically opacifies the lungs in a gravity dependent distribution during PLV. In several infants, radiographs showed only scant traces of perflubron within 48 h after the return to gas ventilation while a few showed residual perflubron several weeks after the last dose. On evaporation, residual PFC may be retained in areas of pulmonary interstitial emphysema that may have not been suspected previously.

Future hope of LV

This aspect was tested mainly in animals and it represents the future hope of LV. Latest research initiatives have suggested the use of PFC for brain cooling, drug delivery, gene transfer or as a contrast agent for ultrasonography of the lung.[3,19]

PFC liquids are useful contrast media. Because they are inert, non-biotransformable and of varying radiopacity, support gas exchange and can be vaporized from the lung, they provide useful diagnostic imaging. Radiographic studies of the perflubron-filled lungs of animals and humans who had CDH have proven informative to show the degree of pulmonary hypoplasia.[6]

Growing evidence from several laboratories suggests that intratracheal administration of PFC liquids may reduce pulmonary inflammation and injury.[6,20]

In virtual bronchoscopy use of the PFC liquid perflubron as a bronchographic contrast agent has enhanced markedly the navigation of substantially more distal airways as small as 0.8 mm.[6]

Delivery of drugs to the lungs by PFCs appears promising. The high solubility of oxygen and carbon dioxide, low surface tension and their ability to enter collapsed lung regions may permit better drug distribution in the diseased lung. PFCs have been studied for delivering antibiotics, anesthetics and vasoactive substances.[21,22]

Because the lung surface area is large (35 times that of the body surface area), the entire cardiac output essentially comes in contact with the pulmonary surface and because the epithelial barrier is thin, the lung is an excellent heat exchanger.[23] As a result of these anatomic and physiologic factors and due to the fact that PFC liquids have a higher heat capacity than conventional gas mixtures, 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.[24,25]

Another hope of LV in neonates is lung protection during cardiopulmonary bypass, which has been tested in animals. Anti-inflammatory effects, avoidance of alveolar collapse, oxygen-carrying capacity and surfactant-like properties may protect the lung before and during cardiopulmonary bypass.[26]

The use of LV in cancer therapy is also investigated. LV may assist the antineoplastic effects of radiotherapy and chemotherapy in the lung by inducing localized hyperthermia or hyperoxia of the lung surface.[5]

Finally, because perfluorochemicals have direct anti-inflammatory effect and alveolar stabilizing effect, they have been tried as potential useful tools for a donor organ preservation prior to lung transplantation.[27] That to determine the degree of pulmonary hypoplasia and to document lend them to radiological applications as well. Low acoustic attenuation makes these liquids well-suited for ultrasound technology while the presence of fluorine makes PFC's useful adjuncts to MRI. Imaging may be useful in infants with structural lung abnormalities like CDH lung expansion over time.[28] Until date, about 900 patients in hospitals, across North America and Europe have been enrolled in LV studies using perflubron. Continuing research in this area should further define the applications and limitations of this alternative clinical approach. Clinical trials have evaluated the possible clinical applications of PLV in the treatment of respiratory failure due to various conditions including persistent pulmonary interstitial emphysema.[29]

CONCLUSION

In spite of advances in respiratory therapy of infants over the past several decades, complications from lung disease remain a major obstacle in neonatal care. The surfactants like properties of PFCs, in combination with the potential for gas exchange during PLV, make it theoretically the ideal treatment for RDS in premature infants. More prospective, randomized controlled studies will allow accurate assessment of the safety, efficacy and relative cost of this technique in adults, children and premature neonates. Further, refinement of PLV strategy is needed before it can be established in the therapeutic field. Potential benefits for the developing countries like India are immense, where HMD is still the major cause of morbidity and mortality.