Long-accepted ventilatory techniques may actually worsen outcomes for ARDS patients. Studies supported by ARDSNet show encouraging results that may improve mortality in this difficult to manage syndrome.

 Today, close to 40% of patients with the adult respiratory distress syndrome (ARDS) do not survive. In the grim arena of ARDS, that is good news. A few years ago, the mortality rate was closer to 70%.1

Researchers, over the past few years, have learned some vital information about ARDS, especially new techniques for ventilating ARDS patients that give those who develop the syndrome a better chance of survival.

Most ARDS mortality is due not to respiratory failure, but to multiple organ dysfunction syndrome (MODS), with a number of failing organs implicated in the patient’s death. ARDS is diagnosed in about 150,000 US patients per year, so any ability to lower the mortality rate is valuable.

Roy Brower, MD, is professor of medicine and medical director of the medical intensive care unit at the Johns Hopkins Medical Institutions, Baltimore. He is a specialist in pulmonary and critical care and a leading investigator of ARDS. In 1996, Brower and a group of colleagues began an important study2 of ventilation in ARDS patients that demonstrated improved mortality and other clinical outcomes among patients who received a mechanical ventilation strategy that was different from the approach that had been commonly used in the past. This work, known as the ARDSNet study because it was performed under the auspices of the ARDS Clinical Network, was completed in 1999, and the results were published in 2000.

The ARDS Clinical Network was organized through the National Heart, Lung, and Blood Institute of the US National Institutes of Health to test agents, devices, and management strategies for ARDS. Brower is a member of the network. What Brower and his fellow researchers determined, essentially, was that traditional ventilation strategies, applied to ARDS patients, could cause additional lung injury and prevent recovery from acute respiratory failure.3,4 Adjustments made in one aspect of mechanical ventilation management to prevent ventilator-induced lung injury could cause complications in other aspects of the care of these patients. That is one reason that ventilatory support for ARDS patients is so demanding.

Brower notes that the mechanical ventilation of ARDS patients has the dual objective of maintaining acceptable gas exchange and “avoiding further injury to the lungs from mechanical forces from the ventilator, but those two objectives are frequently in conflict.” He adds, “We have to prioritize which objective is more important, and sometimes compromise on one for the other.”

Brower continues, “A normal person at rest will have a tidal volume (VT) of about 400 mL. That is about 6 mL per kg of body weight.” Because the lungs of ARDS patients are so compromised, traditional ARDS ventilation techniques called for mechanically delivered VTs about double those seen in normal breathing. The reasoning applied was that the higher VT could compensate for the inefficiencies in gas exchange in ARDS lungs, but evidence mounted that the increased VT could also be hurting the lungs by overdistending them. “With this generous VT, we think the mechanical forces set up additional inflammation and lung injury,” Brower says.

The ARDSNet study2 was designed to compare a VT of 6 mL/kg with the traditional 12 mL/kg. The theory tested was that the less aggressive VT would reduce ventilator-induced lung injury (VILI) and, possibly, save lives. That was what the researchers found. The mortality rate for the ARDS patients in the 6-mL/kg VT group was 31%, as compared with 40% for the group receiving a VT of 12 mL/kg. “The study ended with the conclusion that the lower-VT approach was better for mortality and time on the ventilator,” Brower says. “Therefore, we now say that we ought to adjust our priorities. We ought to make some compromises with respect to the gas-exchange objectives in order to achieve the lung-protection objective.” Brower adds, “When we use a lower VT, if we make no other change besides turning the VT down, then oxygenation will usually fall. The way we compensate for this is by using higher fraction of inspired oxygen (FIO2) and higher levels of positive end-expiratory pressure (PEEP).”

Lung Collapse
Acute respiratory distress syndrome causes the lungs to lose surfactant. “In ARDS,” Brower says, “a number of small bronchioles and alveoli are collapsed at the end of expiration, and then, with inspiration, they may open (and then collapse again). This is mechanically rough on the lungs and can set up additional lung injury—and, for that matter, contribute to MODS.” One way to mitigate this constant opening and closing is to raise the level of PEEP, “which stents those alveoli open,” Brower says. He states that traditional levels of PEEP in ARDS ventilation have been 5 to 12 cm H2O. He notes, “Higher levels of PEEP could also be lung protective, and many studies in models of ARDS suggested that we should ventilate patients with higher levels of PEEP than we used in the past.” Unfortunately, Brower reports, work on the usefulness of higher PEEP in ARDS patients has yielded inconsistent results. Some investigators have suggested that higher PEEP helps against VILI, but others have not. An ARDS Network study on which he worked “could not demonstrate an additional benefit from the higher PEEP in patients who were receiving small tidal volumes, as in the ARDS Network’s earlier study,” Brower says. “The jury is still out on the question, however, and subsequent studies may point toward improved approaches to using PEEP.”

Preventing MODS
The ARDSNet study2 showed that mortality rates improved if VILI from lung overdistension was controlled, but it did not address why VILI might contribute to MODS, the real killer in most ARDS deaths. One investigator attempting to answer this question is Arthur Slutsky, MD, professor of medicine, surgery, and biomedical engineering and director of the interdepartmental division of critical care at the University of Toronto. Slutsky is also vice president of research at St Michael’s Hospital, a teaching hospital affiliated with the university.

Slutsky notes that physicians had long been mystified by the fact that ARDS patients died mostly from MODS. Other patients who required mechanical ventilation, but had not suffered lung injury, could undergo “weeks and months of ventilation, but they did not get MODS.” Why, then, did ARDS progress to MODS? “We hypothesized a few years ago5 that maybe what we do to the lungs with mechanical ventilation to keep the patient alive might actually be a contributing factor,” Slutsky says. He was the principal researcher of a research team6 that set out to test that hypothesis. The team found that VILI could cause the lungs to release toxic mediators, cytokines, and interleukin 8. Blood’s passage through the lungs could then carry harmful substances from the lungs to other organs, damaging them. This could initiate a progression to MODS.

“We showed,” Slutsky says, “that an injurious ventilatory strategy could lead to changes in the kidney that were associated with cell death,” Slutsky says. “We suggested that one of the mechanisms is the molecule folic acid synthesis (Fas) ligand, which can be released from the lungs into the bloodstream; that can then lead to apoptosis.” Slutsky is careful to note that, despite the research linking VILI to MODS, the connection is not fully clear. “We are adding more and more data in support of it, but I would not go to the bank with it, quite frankly,” he says. “There could be something completely unrelated that is causing the end-organ failure.”

Brower takes a similarly cautious approach. “The idea that a lung-protective strategy prevents MODS is a good idea,” he says. “It might even be true.” Both Slutsky and Brower report that antibiotics and other drugs that ARDS patients are given may also play a role in MODS development. “Some of the antibiotics that we give for bad infections are well known to cause renal dysfunction or bone-marrow dysfunction,” Brower says, adding that sepsis itself could also be a contributing factor.

Ventilation in ARDS
Many strategies and techniques for ventilating ARDS patients have been tried and continue to be investigated, but the protocol used in the ARDSNet study2 that employs a lower VT is the only technique that Brower and Slutsky acknowledge has been proven to be safe for generalized adoption, but undoubtedly there will be better strategies that are developed as research progresses. The study’s protocol2 addresses VT, ventilator rates, arterial pH goals, adjustment procedures, plateau-pressure goals, inspiratory flow, and oxygenation, along with PEEP levels and FIO2.
Brower says, “Some people say that there are just too many protocol rules, and that it is impractical to expect clinicians to use those guidelines. If you try it, you will get good at it. It is important that you use a lower VT than you have in the past, and that you monitor plateau pressure and make reasonable adjustments in VT.” Brower reports that the protocol has resulted in better outcomes for his patients and that other institutions that are following their ARDS patients closely are “showing improved outcomes, some of which can be attributed to improved ventilation strategy.”

Slutsky also recommends the ARDSNet protocol.2 When VILI is reduced, the release of toxic mediators is also reduced, he says. “The protocol has essentially decreased mortality, compared with the control group. It uses smaller VT, and it titrates the PEEP according to the oxygenation of the patient. It is a good start, but there are some caveats there.” If a patient has a stiff chest wall, for instance, Slutsky states that the lower VT may be too small. The hard truth, he adds, is that ARDS is such a difficult condition to deal with that there may be no optimal ventilation strategy in which gain in one area is not offset by loss in another. “ARDS patients are very hard to ventilate. They have areas of the lung that are full of fluid, and the lungs are stiff; there are also atelectatic or collapsed areas. In some patients, no matter what you do, there are going to be some lung units put under increased stress and prone to injury,” he says.

One technique that Slutsky finds may help severely compromised ARDS patients is prone positioning. “That might lead to a decrease in VILI,” he says. “There are some data to suggest that it might decrease mortality, but that has not been proven yet.” So far, Slutsky adds, no ventilation strategies have been invented for ARDS patients with different characteristics (for example, for those of different ages, or for trauma patients as opposed to those with sepsis).

The Future
Pulmonologists are certainly trying new techniques to ventilate ARDS patients and to keep them from progressing to MODS. Both Brower and Slutsky hope that the use of higher PEEP, which has been useful in animal models, will prove beneficial as an injury-reduction technique in humans, but more research (which is under way ) is needed. The same can be said for high-frequency ventilation. “If it is useful, it will probably be only in patients with ARDS,” Brower says, “but if we adopt this approach, it is going to be rather expensive, and it is important to demonstrate that this technique will improve clinical outcomes before we commit to it.”

Slutsky reports that another way of preventing MODS in ARDS patients may come with the development of substances that block the emission of VILI-induced toxins before they get into the bloodstream or mitigate their effect once they do get into the circulation. Then, the toxins could not harm other organs and lead to MODS. “One way might be to use something that mops up soluble Fas ligand,” he says, “whether it is an antibody or a fusion protein. In a study6 in a cell-culture model, we did use a fusion protein to bind to Fas ligand.”

Other approaches being tried are intermittent deep-breath ventilation (to recruit more of the lungs for oxygenation) and tracheal gas insufflation, which supplies gas through a small catheter in the endotracheal tube and produces a very low VT.

Both Brower and Slutsky note that extracorporeal oxygenation devices that control oxygen and carbon dioxide levels in the blood without involving the lungs could someday help ARDS patients. “A group is developing a way to do that inside the human so that the blood does not have to go outside the body, but it is still very experimental,” Slutsky says. Given the difficulty of ARDS ventilation, however, clinicians are likely to welcome all the help that they can get.

George Wiley is a contributing writer for RT.

1. ARDS Foundation. Facts about ARDS. Available at: http://www.ardsil.com/facts.htm#5. Accessed January 6, 2005.
2. ARDSNet. Current and completed
studies. Respiratory management in ALI/ARDS. Available at: http://www.ardsnet.org/ards01.php. Accessed January 6, 2005.
3. Brower RG, Shanholtz CB, Fessler HE, et al. Small tidal volume ventilation in ARDS: results of a randomized controlled trial. Crit Care Med. 1999;27:1492-8.
4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-8.
5. Slutsky AS, Tremblay LN. Multiple system organ failure: Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med. 1998;157:1721-1725.
6. Imai Y, Parado J, Kajikawa O, et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA. 2003;289:2104-2.