Liquid Ventilation: The Way of the Future

Catherine Baresich RRT

Term Paper (April 1997)
Respiratory Therapy Program
Fanshawe College
London, Ontario, Canada
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Abstract

A major cause of morbidity and mortality in pediatric and adult patients is acute respiratory distress syndrome (ARDS), which may require treatment with the use of mechanical ventilation. Refinement of conventional mechanical ventilation techniques have not sufficiently addressed the issues of oxygen toxicity and barotrauma incurred by the patient due to this method of treatment. Furthermore, the other techniques used to improve oxygenation in ARDS, such as nitric oxide, may not cause a significant improvement in a large portion of patients.

Over the past thirty years, the idea of using liquids to improve ventilation in respiratory distress has been experimented with by several researchers. In the 1960's, a synthetic fluorocarbon was discovered to be an excellent oxygen carrier. Researchers have concentrated on the therapeutic use of fluorocarbons and the potential role they may play in improving the survival rate of patients with ARDS. Recent studies using perflubron have shown that liquid ventilation results in improved oxygenation and lung mechanics which reduces intrapulmonary shunting and atelectasis. Also, other properties of perflubrons such as low toxicity and low miscibility with other substances, makes it an ideal substance to be used in the body.

The purpose of this paper is to define ARDS, review the history of liquid ventilation, examine the physical properties and delivery techniques of perflubrons and analyze the clinical experience of liquid ventilation.

Liquid breathing may be the innovation that will begin an important new approach to supporting gas exchange in the acutely injured lung. There are still a number of important questions that remain to be answered, but the answers to these questions require further clinical study using liquid ventilation therapy to determine whether it will significantly change the outcome of ARDS in critically ill patients.

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Key words: fluorocarbons, liquid breathing, mechanical ventilation, acute respiratory distress syndrome, oxygen toxicity, pulmonary gas exchange.

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Introduction

Despite advances in technology, acute respiratory distress syndrome (ARDS) remains to be difficult to treat in both pediatric and adult populations. Conventional mechanical ventilation and other therapies, including high frequency ventilation, surfactant replacement therapy, nitric oxide and extracorporeal membrane oxygenation (ECMO) have lifesaving innovations for many patients suffering from this acute lung disease. However, there still remains a significant patient population that doesn't respond to therapy or the therapy is inappropriate for that particular patient.

ARDS is an acute disease process that involves the lung parenchyma. Severe infection, trauma or systemic illness has caused a progressive deterioration in lung function. This condition is often found in patients who have no previous history of chronic lung disease. Clinical features of the syndrome include cyanosis refractory to oxygen therapy, tachypnea, dyspnea, atelectasis., increased intrapulmonary shunting, decreased lung compliance, decreased lung volumes, pulmonary edema, hemorrhage, hyaline membrane formation and diffuse alveolar infiltrates.¹ Clinical management of ARDS involves treatment of the underlying disease process as well as maintaining sufficient tissue oxygenation.

To improve oxygenation, several techniques have been employed, including the use of volume and pressure limited ventilation, positive end expiratory pressure (PEEP), prone positioning, inverse I:E ratios and high inspired oxygen concentrations. However, the iatrogenic effects of mechanical ventilation and high levels of inspired oxygen may cause further lung injury as a result of barotrauma and oxygen toxicity. Furthermore, neonatal patients may suffer lifelong pulmonary and neurologic disabilities (bronchopulmonarydyspasia, intracranial hemorrhage and hearing loss) due to mechanical ventilation.

Surfactant replacement therapy has been used with success in neonatal patients. In neonates, ARDS is caused by a lack of surfactant due to prematurity of the lungs. In the adult patients, surfactant deficiency is accompanied by pulmonary edema due to an acute cause. The use of surfactant in adult patients hasn't been as successful.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, decreases pulmonary hypertension and improves arterial oxygenation. NO is toxic at high levels, therefore, the systemic effects and long-term use of NO requires further study.

ECMO circulates blood through a membrane outside the body in order to oxygenate the blood and remove carbon dioxide. Premature infants have an increased risk of intraventricular hemorrhage as well as technical difficulties, such as large bore catheters required to cannulate vessels, that limit the use of ECMO. Other disadvantages of ECMO are: invasiveness of the procedure, bleeding, the need for continuous anticoagulation, and cost. Also, large blood bank stores, expensive equipment and specially trained personnel are required to manage the ECMO procedure.

The disadvantages and unsuccessfulness of these therapies have rekindled an interest in finding new methods of supporting gas exchange in the acutely injured lung, as well as decreasing the incidence of trauma due to conventional therapy. One such method is liquid ventilation.

History

Liquid ventilation is an old concept that dates back to 1920 when Winternitz and Smith showed that the lungs can tolerate large volumes of saline solution with no damage.² Neergard's experiment indicated that lung compliance was improved by saline lavage.² West demonstrated a relationship between pulmonary ventilation and blood flow.² He demonstrated that blood flow distribution was improved and more uniform in lungs that were ventilated with saline solution and gas when compared to gas alone. The limiting factor in all these studies was the inability to oxygenate the animals in order to sustain life. This direction of research was abandoned and almost forgotten.

In 1950, Stein and Sonnenschein suggested that animal life could be sustained when submerged in hyperbarically oxygenated saline solution.² In 1962, Krystla demonstrated the short term survival of mice that were submerged in the hyperbarically oxygenated saline.² Up to this point, investigation of liquid ventilation had been slow due to concentration on gas ventilation.

Clark and Gollan established the remarkable gas exchange qualities of perfluorocarbons (PFC) in 1966. Their experiment involved submersing spontaneously breathing mice in a substance known as FX-80, (a PFC produced by 3M, St Paul, Minnesota). The animals sustained life while immersed in the liquid and survived after return to gas breathing. This experiment was the breakthrough required for further investigation of the use of PFC for support of gas exchange in the lung.

Physical Properties

PFC liquids have many qualities that are unique and make them perfect for liquid ventilation. PFC liquids are nontoxic, biocompatible and aren't absorbed by tissues. They are odourless, colourless fluids that have the same consistency and appearance of water. PFC liquids have ¹/₄ the surface tension, 16 times the oxygen solubility and 3 times the carbon dioxide solubility of water.

PFC liquids are structurally similar to hydrocarbons, with the hydrogen replaced by fluorine. The carbon chains vary in length and an additional molecule gives unique properties to each PFC.

PFC liquids are unique in that they have an exceptionally strong affinity for gases. Oxygen and carbon dioxide readily dissolve in the liquid. This gives PFC liquids an excellent oxygen and carbon dioxide carrying capacity; 50 ml of oxygen per dL and 160 - 210 ml of carbon dioxide per dL. PFC liquids have a slightly less carrying capacity of oxygen compared to blood, up to 200 mmHg. But beyond 200mmHg, PFC liquids are actually better.

Another trait that makes PFC liquids suitable for liquid ventilation is its high spreading coefficient. These liquids have a very low surface tension (approximately 18 - 19 dynes/cm), and act similarly to surfactant when instilled in the lung. When instilled, the PFC spreads into the collapsed alveoli where gases were not able to penetrate before and lines the alveolus, stabilizing and re-expanding it. Gas exchange occurs across the liquid to liquid interface. Animal studies have shown the dramatic improvement in gas exchange, pulmonary mechanics and ventilation-perfusion matching that is due to the increase in alveolar stability.^{3, 4} Also significant was the improvement in the respiratory function upon return to gas ventilation.

PFC liquids are twice as dense as water. The weight of the PFC causes it to flow to the dependent regions of the lung, which are most likely to have atelectasis. These collapsed, dependent regions of the lung contribute to the physiological shunt that occurs during gas ventilation. The liquid splints open the collapsed alveoli much like PEEP. Cross-sectional imaging has revealed the there is homogenous distribution of the PFC during liquid ventilation when compared to gas ventilation.⁵ It has been hypothesized that a second effect is at work that further improves ventilation-perfusion matching; the weight of the PFC liquid redirect blood flow to the nondependent, better ventilated lung segments. By doing so, pulmonary blood flow is redistributed to less severely injured/collapsed areas of the lungs with an associated improvement in ventilation-perfusion matching. The unique properties of PFC liquids to decrease surface tension, recruit and stabilize alveoli, improve gas exchange, lower peak airway pressures and improve lung compliance has indicated that liquid ventilation can reduce intrapulmonary shunting and atelectasis..⁶

Because PFC liquids are very dense, airway resistance to the liquid tidal volume is very high, causing the work of breathing to be very high. Thus, liquid ventilation requires the use of a mechanical breathing device to assist breathing.

Oxygen and carbon dioxide readily dissolve in PFC liquids, while other substances do not mix well with it. PFCs can transport gases and liquids without combining with them or altering them. This makes is a perfect medium for delivery of other substances that work in the lungs, such as mucolytics and/or bronchodilators, and therefore has created great interest in this area.

Surfactant isn't removed from the lungs by PFC liquids, nor does it mix with or absorb the PFC liquid.⁷ Leach confirmed this, as well as an improvement in oxygenation and lung compliance by liquid ventilation, but showed that there was no increased efficacy with additional doses of surfactant.⁸

Wilcox also demonstrated improved gas exchange and lung compliance while using liquid ventilation in lambs born with congenital diaphragmatic hernia.² NO was also administered to the animals, and within 10 minutes, an increase in oxygenation was noted. Since NO decreases pulmonary vascular resistance, right to left shunting is reduced and oxygenation improves. As well, by decreasing the hypoxic trigger for constriction, further pulmonary vasodilation may result, thereby, further decreasing the pulmonary vascular resistance.

Liquid ventilation is very effective at breaking up mucus plugs and mobilizing them. PFC liquids don't hydrate inspissated secretions and helps wash them out of the lungs. Any aspirated or exudative debris will float to the top of the PFC where it can be suctioned out of the lungs.

Shaffer's and Hirschl's experiments using meconium stained lambs indicates that PFC liquids can be used to remove the tenacious meconium from the lungs by floating it to the surface and into larger airways where it can be then removed by suctioning.^9,10 Improvements were noted in the A-a gradient, compliance and the blood flow was more uniform. In addition, PaCO₂ was lowered during liquid ventilation and it was concluded that liquid ventilation improved pulmonary perfusion and ventilation/perfusion matching.

Hirschl described a study where a woman developed ARDS after aspirating charcoal given to neutralize ingestion of a drug.¹¹ Repeated saline lavage wasn't successful in removing the charcoal, but with liquid ventilation the charcoal floated to the top of the PFC and was suctioned out of the lungs. There was a dramatic improvement in the patient after the initiation of liquid ventilation.

The density of PFC provides a very good x-ray marker. It allows a chest x-ray to be more defined, as well as making it easier to keep track of filling and distribution of the PFC in the lung. Liquid ventilation can assist in the diagnosis of atelectasis, pneumothorax, airway obstructions and tumors. The drawback is that it obscures the endotracheal tube (ETT), chest tube and pulmonary catheter placement. It also blocks out organs such as the heart, that are in the same vicinity as the lungs.

PFC liquids have a high vapour pressure and are removed from the body by simple evaporation. There may be traces of the PFC months to years after a trial of liquid ventilation, but most of the PFC evaporates from the lung within days.

There has been extensive research into the toxicity of PFC liquids. It has been shown that there are no ill effects to mature or premature animals and humans. Investigators observed lab animals for up to 3 years after a trial of liquid ventilation.² There were no behavioural differences noted, and measurement of lung mechanics, function and gas exchange were indistinguishable between the control group and experimental group. At the time of sacrifice, examination of the lung revealed traces of PFC 3 years after the trial of liquid ventilation. Small amounts were also found systemically in the heart, brain, muscle, liver, kidney, spleen and especially in adipose tissue. Inspection of the lung demonstrated patent airways and intact parenchyma of normal colour and consistency. There is now evidence that suggests that residual PFC is removed via pinocytosis by alveolar macrophages. From these studies it was concluded that liquid ventilation can be administered successfully and safely.

Comparison of the lungs of preterm lambs in a liquid ventilated group to a group that received only gas ventilation revealed significant differences. Wolfson noted that the lungs of the two different groups were histologically different.¹² The lungs of the liquid ventilated group appeared normal and uniformly expanded. Fig 3.¹³ There was no evidence of hemorrhage, hyaline membranes or thickening of alveolar wall. The wall of the gas ventilated group had thickening as well as hemorrhaging, hyaline membranes and the lungs looked "liver-like",.¹³

While investigating the distribution of PFCs in the lung, a surprising, yet fairly reproducible finding was discovered. Animals with induced ARDS showed a reduction in the degree of lung injury and inflammatory infiltrate observed during liquid ventilation when compared to gas ventilation.² PFC liquids may reduce the risk of infection in the lungs by not providing any nutrition for the bacterial and washing exudative debris out of the lung thereby reducing the incidence of bacterial growth.

Delivery Techniques

Early investigation of liquid ventilation focused on the delivery of the liquid. At first, spontaneously breathing animals were submerged in the PFC liquid. Researchers noted that the animals adapted by slowing their breathing rate down to 5 to 8 breaths per minute and had prolonged inspiratory and expiratory times. The researchers concluded that due to the high viscosity of the liquid compare to gas, the work of breathing was greatly increased. At these slow rates, adequate carbon dioxide elimination wasn't possible and respiratory acidosis occurred. After a few hours, the animals were physically exhausted and couldn't continue to breath.

The first generation of delivery systems used gravity to obtain tidal movement of the PFC liquid in and out of the lungs. A heated, oxygenated reservoir of PFC liquid was suspended above the animal attached to the ETT by a Y-piece. The outport of the Y-connector was connected to an expiratory reservoir below the animal. Filling and emptying cycles were accomplished by raising and lowering the suspended reservoir. However, the build-up of carbon dioxide remained a concern. The problem was caused by expiratory flow and diffusion limitations due to ineffective methods of mechanical ventilation.

In 1974, Moskowitz and Shaffer introduced and refined a demand-regulated liquid ventilator.² This method of controlled ventilation established a tidal volume and respiratory rate and decreased the work of breathing by providing mechanical assistance. This system provided effective oxygenation and better carbon dioxide removal. The lungs were filled to an amount equal to to the FRC (approximately 30 ml/kg) and the "liquid ventilator" was used to generate tidal breathing of the PFC liquid. A monitoring system allowed the measurement of tidal volumes so the optimal clearance of carbon dioxide could be attained. Optimal carbon dioxide clearance was achieved at a respiratory rate of 4-5 breaths per minute and typical tidal volumes were in the range of 15-20 ml/kg.

In 1991, Curtis described the use of a continuous flow liquid ventilator which had a roller pump that could be used to change tidal volume, inspiratory time and breaths per minute.² Hirschl described a flow limited, time cycled liquid ventilator system that was adapted from an extracorporeal life support circuit.¹⁴ This method allowed for control of tidal volume, airway and alveolar pressure and FRC.

The method of liquid ventilation described so far is called total liquid ventilation (TLV). TLV may provide the lowest alveolar pressures in order to limit barotrauma in the lung. Another advantage of TLV is that exudate is very effectively lavaged from the airways. In addition, the distribution of PFC in the lungs may be more uniform in TLV. However, this method is limited by the rate and tidal volume that can be delivered.

Clinical Experience

The first human trials were conducted in 1989 by Greenspan as a rescue therapy for three infants with severe RDS.¹⁵ The infants had not benefited from surfactant therapy and were considered near death. All three infants eventually died within nineteen hours of the trial of liquid ventilation, but the cause of death was thought to be due to the severity of the disease and was not related to the liquid ventilation.

After the trial of liquid ventilation, each infant demonstrated a significant improvement in lung compliance by more than 60% within one hour and two of the infants experienced an improvement in oxygenation. During the trial, hemodynamic measurements remained stable. Their study showed that liquid ventilation was able to support gas exchange as well as a residual improvement in pulmonary function following return to gas ventilation in the critically ill.

The most recent innovation in liquid ventilation uses gas tidal volumes with a liquid-filled FRC (30ml/kg). In 1991, Fuhrman described this simpler method and called it perfluorocarbon-associated gas exchange (PAGE).² PAGE or partial liquid ventilation (PLO) is less less expensive and less complex than LTV and represents the method of liquid ventilation that is most commonly used. Liquid resistance to flow is minimized while oxygenation and carbon dioxide elimination are manipulated using the same techniques as gas ventilation. This method doesn't require the use of a complex liquid ventilator setup. Adequate gas exchange was achieved with the use of a conventional mechanical ventilator delivering tidal volumes of 10-15 ml/kg. The adequacy of the PFC dose is assessed by visually identifying a meniscus of PFC within the ET at end-exhalation.

Encouraging results of recent pilot studies using PLO as a treatment for severe respiratory distress have generated tremendous interest in this technology. These studies have shown PLO and LTV to have marked improvement in gas exchange and pulmonary function in premature lambs with RDAs, neonatal piglets with gastric acid aspiration, saline lavaged rabbits, oleic acid injured dogs, and saline lavaged, oleic acid injured sheep.¹⁶

In a multicenter study of 13 seriously injured premature infants, Leach described dramatic improvement in compliance and oxygenation within 20 hours of treatment with PLV.¹⁷ At the University of Michigan, Hirschl assessed the safety and efficacy of PLV in a group of 19 adults, children and neonates whose severe respiratory failure required extracorporeal life support (ECLS).^18,19 Another study demonstrated the potential of PLV to improve gas exchange and pulmonary compliance in newborn patients with congenital diaphragmatic hernia.²⁰ By using ECMO to stabilize the patient, the researchers were able to confirm improvements in gas exchange, physiological shunt and lung compliance. They have demonstrated that all patients tolerated the PLV with no hemodynamic compromise. Similar studies have suggested that PLV is safe and effective in improving gas exchange in adult, pediatric and premature newborn patients with respiratory insufficiency who aren't on ECMO.

Although liquid ventilation has many beneficial effects and is safe to use, there are potential complications which include pneumothorax, escape of perfluocarbon into the pleural space and mucus plugging.

Patient Management

A patient undergoing PLV may receive several doses a day of PFC, but the therapy is usually limited to a few days. Many specifics of the therapy, such as amount of PFC used, number of times the patient is dosed, and time frame between doses are presently dictated by the investigational research protocol.

Conclusion

It is clear that liquid ventilation is at an early stage in its clinical evolution, but substantial progress has been made in the development and evaluation of this new method of ventilation. Certainly, it will play a role in the treatment of patients with acute lung injury that are unresponsive to conventional therapy.

Clinical trials have demonstrated improved gas exchange, decreased airway pressures, and increased lung compliance in preterm infants, newborns and adults with severe pulmonary disease. Liquid ventilation has the potential to treat pulmonary disease with less trauma to the lungs and also compliments other therapies such as ECMO and NO. Furthermore, liquid ventilation has been shown to decrease inflammatory response, improve atelectasis and reduce intrapulmonary shunting. Current research has demonstrated that liquid ventilation can be safely administered to patients without serious side effects, but continued study must be performed in order to determine the efficacy and cost of this technology in prospective patient populations. All of these findings have lead to the conclusion that liquid ventilation is nearly a perfect therapy for patients experiencing respiratory insufficiency. Hopefully, liquid ventilation will become a standard form of therapy for respiratory distress instead of its current use as a rescue therapy.

[abstract] [introduction] [history] [physical properties] [delivery techniques]
[clinical experience] [patient management] [conclusion]

References

[abstract] [introduction] [history] [physical properties] [delivery techniques]
[clinical experience] [patient management] [conclusion]

© 1997 Respiratory Therapy Society of Ontario (RTSO)