Ventilation and ARDS

by George Wiley

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.