Although as yet controversial, liquid ventilation?both total and partial?may be the best solution to eliminating ventilator induced lung injury, which can be a result of mechanical ventilation and can lead to organ failure in ARDS patients.

 Conventional treatment of adult respiratory distress syndrome (ARDS)—the often-fatal disorder characterized by severe refractory hypoxemia, noncardiogenic pulmonary edema, and stiff, noncompliant lungs—revolves around use of flow-controlled, volume-cycled mechanical ventilation with positive end-expiratory pressure (PEEP). However, this approach to therapy sometimes triggers a secondary insult known as ventilator-induced lung injury (VILI).

“Mechanical ventilation at certain settings can worsen lung inflammation and lead to organ failure in ARDS patients,” says Herbert P. Wiedemann, MD, chairman of the Department of Pulmonary, Allergy, and Critical Care Medicine at Cleveland Clinic Foundation in Cleveland, an authority on ARDS and ventilator injury.

Wiedemann explains there are two hypotheses as to how VILI occurs. The first fixes blame on overdistension—the “volutrauma hypothesis” as it is known in some circles.

“Chest CT scans and microscopic histologies of ARDS patients reveal areas of significant lung injury and consolidation,” he begins. “These are collapsed alveolar spaces not participating in ventilation, and they are located alongside or in proximity to normal or relatively normal lung units. As such, giving conventional tidal volumes of 10 ml to 15 ml per kg of body weight to these patients probably results in most or all of the tidal volume by preference flowing to a small, proportional, normal-compliant lung and not into the injured lung. From this, you can have the possibility of overdistending the normal lung units.”

The second hypothesis of how VILI can occur with mechanical ventilation of the ARDS patient holds that repetitive closure and reopening of lung units cause atelectasis trauma.

“At end expiration, a large number of lung units are collapsed, even when some degree of PEEP is administered; with the next inspiratory breath, those collapsed units must be forced open and that is what is thought to produce atelectasis trauma,” says Wiedemann.

Regardless of which hypothesis is correct, Wiedemann notes that VILI represents an inflammatory lung injury that is worsened with continuation of the mechanical ventilation. “The lung injury perpetuates and, eventually, the inflammation spills over into the circulatory system,” he says. “That causes the organ failures of which people with ARDS typically die.”

Improving Gas Exchange
VILI can be addressed in any of several ways, Wiedemann reports. For example: using lower tidal volumes, which, he says, has been shown to prevent overdistension.

“The downside to lower tidal volumes is, of course, worsened gas exchange—less oxygenation of the blood and higher blood CO2 levels,” says Wiedemann.

Perhaps the most intriguing—and controversial—approach involves liquid ventilation.

“In theory, liquid ventilation should be an appreciably safer form of ventilation for ARDS patients, although that theory remains to be borne out by clinical testing,” says Wiedemann.

There are two forms of liquid ventilation—total and partial. Both employ perfluorocarbon (PFC), a heavy, inert liquid with high gas solubility for oxygen and carbon dioxide and wholly lacking the ability to mix with water (a number of different PFCs have been developed; each has its own unique properties in accordance with the particular length of its carbon chain).

In total liquid ventilation, PFC is introduced to the lungs, filling them to a volume of about 30 ml per kg of body weight (the equivalent of the lungs’ functional residual capacity). A machine specially designed to circulate the PFC initiates and maintains tidal breathing. The machine is typically set for tidal volume of between 15 ml and 20 ml per kg of body weight, Wiedemann indicates.

Partial liquid ventilation likewise entails filling the lungs to functional residual capacity (at least initially) with PFC, but instead relies on an ordinary mechanical ventilator to supply tidal breathing. This is considered the easier and by far less costly of the two techniques (mainly because it can be accomplished with ventilators already on hand).

“Liquid ventilation has been around—at least conceptually—since the early 1960s when the impressive gas-exchange properties of PFC were observed in laboratory experiments involving mice.” Wiedemann says.

The first clinical evaluation of PFC in humans took place in 1990. That year, three newborns—all premature and moribund—received PFC to lavage their lungs. Two of the three babies shortly thereafter showed improvements in gas exchange and pulmonary function.

“The idea behind treating ARDS with liquid ventilation is that the PFC will get into the lung units—especially those dependent lung units that often remain closed despite conventional mechanical ventilation and PEEP—and will wash out much of the inflammatory debris,” says Wiedemann. “Indeed, when a patient starts liquid ventilation, there is commonly a significant amount of mucoid material expelled from the lung. This is material you would otherwise never get out. Certainly in animal models and in many patients, gas exchange improves and the amount of shunt hypoxemia is reduced.”

In addition to observing these mechanical effects of recruiting lung units and improving gas exchange, a number of investigators over the years have documented that PFC also possesses anti-inflammatory properties. For example, one version of PFC—the drug perflubron—was shown in vitro to reduce the amount of proinflammatory cytokines released from stimulated human alveolar macrophages.1

Unfortunately, the efficacy of PFC and liquid ventilation in the treatment or prevention of ARDS has not been substantiated in clinical testing. The most important ARDS-specific liquid ventilation clinical trial to date was one led by Wiedemann in 1999-2000. He and his colleagues at other participating centers around the country divided a cohort of approximately 300 ARDS patients into three equal groups, with one receiving conventional mechanical ventilation, the second low-dose perflubron-based liquid ventilation, and the third a high dose of the same. The findings of that multi-center investigation were not terribly encouraging.

“The results were essentially negative,” he recounts. “Liquid ventilation in this study had no overall effect on either mortality or ventilator-free days.”

Details of that trial are only now about to be formally reported in an article slated to appear in a coming issue of the American Journal of Respiratory and Critical Care Medicine.

Worth Another Try?
Wiedemann confesses puzzlement as to why perflubron did not work as expected in his clinical trial. He postulates, however, that the disappointing performance might have been attributable to use of unadvisedly high tidal-volume settings on the mechanical ventilators that were employed.

“It’s important to remember that the clinical trial I led started before the results of another VILI investigation dealing specifically with tidal volume were known,” he says.

The study to which he makes reference was published in the New England Journal of Medicine.2 It demonstrated that ventilating with 6 ml per kg of ideal body weight was superior to ventilating with 12 ml per kg of ideal body weight.

“The mortality rate in the lower tidal-volume group was 31%, compared to 40% in the higher tidal-volume group,” Wiedemann says. “It validated the volutrauma hypothesis of VILI, and showed that lower tidal volumes can reduce lung injury—that is, it can reduce lung inflammation, reduce systemic inflammation, and reduce organ failures.”

That, he says, then begs the question: could liquid ventilation be effective if used with a different and more optimized approach to mechanical ventilation? Alas, it may be a very long time before the answer is known because no one at present is proposing to explore the matter via clinical trial.

“Industry isn’t willing to sponsor such a study without some indication of a better likelihood of success,” Wiedemann laments.

This lack of industry enthusiasm is especially troubling to some proponents of liquid ventilation, given their conviction that liquid ventilation might also prove an ideal mechanism for more efficient and effective delivery of antibiotics or gene therapeutics into the lungs.

“It’s all very experimental at this time, but, in animal studies at least, the delivery of gene therapy to the lung epithelium, down at the alveolar level where there is a Type I pneumocyte, is enhanced if linked to liquid ventilation,” Wiedemann says. “It’s believed this enhancement of delivery is owed to the ability of perflubron to open up more lung units and push material more distally.”

Another approach to ARDS treatment currently receiving attention is surfactant replacement therapy. Here again, liquid ventilation might play a role, thanks to the favorable surface-tension characteristics of PFCs (18 to 19 dynes per centimeter).

“Early in lung injury, the pathophysiology of ARDS is such that surfactant rapidly becomes inactivated by plasma proteins,” Wiedemann says. “This can manifest as capillary leak edema. The problem perpetuates as the alveolar units collapse, with the result being more atelectasis and shunt hypoxemia. Of concern too is the way this rapid inactivation of surfactant contributes to creation of an environment in which proinflammatory events can proceed and cascade is much easier.

“At least in vitro, we can overcome this inactivation of surfactant and inflammation cascade by increasing the concentration of surfactant.”

Wiedemann indicates there have so far been several clinical trials in which various surfactant replacements other than PFC have been given to ARDS patients, but none has shown notably great promise. He says that is not surprising, “given the complexity of surfactants, what with all their many protein constituents and lipid components.”

Research Funding
Some of the most promising research into ARDS-related VILI treatment and prevention originates these days with an entity known as the ARDS Clinical Network—ARDSNet, for short—which is funded and directed by the National Institutes of Health through its National Heart, Lung and Blood Institute (NHLBI).

ARDSNet started in 1994. Today, it includes 18 clinical centers (comprised of 42 hospitals) and one clinical coordinating center. Each clinical center is assigned a principal investigator who, together with the NHLBI’s project scientist, forms a steering committee for the network as a whole.

“The steering committee identifies promising new agents for the treatment of ARDS, sets priorities, develops protocols, facilitates the conduct and monitoring of the clinical trials, and reports the study results,” says Wiedemann. “A protocol review committee provides an independent scientific evaluation for the NHLBI on each new protocol that is developed. A data and safety monitoring board advises the NHLBI on data quality and analysis, and ethical and human subject aspects of each trial. Meanwhile, an electronic data collection system has been established by the clinical coordinating center to facilitate ease of data management and communication among the ARDSNet hospitals.”

The original NIH funding mandate came to a close not long ago. It was subsequently renewed, so the work of ARDSNet continues (all of the clinical trials and other activities under the original funding mandate thus are ascribed as belonging to ARDSNet 1, while those trials covered by the new funding mandate are designated as projects under ARDSNet 2).

“ARDSNet 2 trials expected to take place include an investigation of high-

frequency oscillatory ventilation,” says Wiedemann. “And, currently, ARDSNet 2 is conducting a clinical trial examining two different strategies for managing intravenous fluids and fluid balance in patients with acute lung injury.”

Wiedemann says ARDSNet is an entity with which respiratory therapists should be acquainted because so much of the research has a bearing on issues of daily clinical practice (including mechanical ventilation tidal volume and PEEP). “ARDSNet has mainly shown the importance of the ventilator and its settings in ARDS treatment and prevention,” he says.

Respiratory therapists curious about ARDSNet and results of the various clinical trials (plus their protocols) can visit the organization’s Web site at

Rich Smith is a contributing writer for RT.

1. Thomassen MJ, Buhrow LT, Wiedemann HP. Perflubron decreases inflammatory cytokine production by human alveolar macrophages. Crit Care Med. 1997;25:2045-2047. Available at: Accessed on November 8, 2005.
2. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308.