Efficacy and Safety of a Lung Recruitment Protocol in Children With Acute Lung Injury

I. Introduction A. Background Lung units which participate in gas exchange are known as
'recruited' lung. Patients with lung injury suffer from a proportion of units which do not
participate in gas exchange (i.e. the derecruited state), at times resulting in impaired gas
exchange. Derecruitment of alveoli may also cause intrapulmonary shunting and worsen lung
injury through atelectotrauma7. Outcomes in acute respiratory distress syndrome have
improved significantly Is this really true? since clinicians have begun to employ lung
protective strategies, including low-tidal volume ventilation and permissive hypercapnea8,
9. However, low-tidal volume ventilation has been recognized to decrease recruited lung
volume, a phenomenon which persists despite the aggressive positive end-expiratory pressure
(PEEP) strategy employed in ARDSNet studies4. Atelectasis associated with low-tidal volume
ventilation is relieved through the use of so-called sign breaths, or recruitment breaths10.
Further, the proportion of lung remaining in the derecruited state may contribute to the
morbidity and mortality associated with acute respiratory distress syndrome (ARDS)11. In
adults, several strategies have been utilized to recruit the lung: sustained inflation (SI)
and the maximal recruitment strategy. The so-called open lung approach (OLA) includes an SI
followed by the setting of PEEP to the measured lower inflection point of the PV curve. An
alternative approach to setting PEEP is a decremental PEEP titration, which includes the
sequential lowering of PEEP until a predetermined decrement in PaO2 or SaO2 occurs. Studies
which have not included a strategy for maintaining lung recruitment following a recruitment
maneuver have all been studied.

The impact of lung recruitment in the long-term course of ARDS is not yet clear. It is
clear that lung recruitment is most effective earlier in the course of ALI/ARDS. Grasso et
al demonstrated that patients who received a recruitment maneuver on day 1±0.3 of ARDS could
be recruited, versus patients recruited on day 7±1. Similarly, Gattinoni et al11 and Crotti
et al5 found limited recruitment in patients who were well along in the course of ARDS.
Borges et al,6 Tugrul et al,12 and Girgis et al all recruited patients early in the course
of ARDS, and each found marked lung recruitment, on average, in all the patients studied.
Each of these studied demonstrated an ability to improve oxygen saturations and (sometimes
studied) end-expiratory lung volume. While no study has examined the effect of this change
on morbidity or mortality, in children hypoxemia is known to be a common cause of morbidity.
Importantly in children, treatment of hypoxia often drives escalating ventilator settings,
the use of high frequency oscillatory ventilation (HFOV) or the use of extra-corporeal
membrane oxygenation (ECMO). Early recruitment in children with ALI/ARDS may prevent the
need for escalation of care towards these more invasive, and risk-imposing therapies.

Currently, there are no clinical practice guidelines or standard of care regarding lung
recruitment strategies for children with lung injury. To date, no studies have been
performed in children documenting the efficacy or safety of any of the strategies utilized
in intensive care. The primary aim of this study is to demonstrate the efficacy and safety
of sustained inflation and maximal recruitment maneuvers in children with lung injury.

B. Lung Recruitment Maneuvers

1. Sustained Inflations (SI) Sustained inflations (SI) are commonly utilized in the
intensive care unit as a recruitment maneuver. In SI, the patient is given a prolonged
positive pressure breath (usually between 30 and 45 cm H2O) lasting between 15 and 40
seconds. Clinically, this maneuver is applied following a derecruitment, such as
suctioning, or when the patient exhibits hypoxemia. This strategy is currently
employed in the Children's Hospital Boston Medical-Surgical Intensive Care Unit in some
patients with lung injury, though there is no published evidence of its safety or
efficacy in children. Could we put the 3 SI studies in premature infants that use 20-40
cmH20 followed by CPAP? 1 was a rabbit study. The studies described below regard
sustained inflation recruitment maneuvers.

1. Tugrul, et al12 studied the effect of SI in 24 adults with ARDS. SI included 45
cm H2O for 30 seconds, followed by a decremental PEEP titration from 20 cm H2O
down, titrating to saturations. P/F ratio increased >200 in 11/24 patients, which
persisted at 6 hours post-maneuver in 9/24 patients. Barotrauma was not observed
in any patients.

2. Richard, et al studied4 the effect of SI (45 cm H2O for 15 seconds) in 10 adults
with ARDS ventilated with a low-tidal volume strategy. The maneuver induced a
significant increase in recruited lung volumes (175±108 ml pre-maneuver versus
254±137 ml post-maneuver). This improvement was associated with an increase in
arterial oxygen saturations. There was no report of sustainability of
recruitment, nor of adverse effects.

3. Lapinski, et al13 studied the safety and efficacy of the SI maneuver in 14 adults
with ARDS. The pressure utilized in the maneuver was the lesser of 45 cm H2O or
the plateau pressure utilized in 12 mL/kg tidal volume breaths; the maneuver was
held for 20 seconds. Oxygen saturations increased from 86.9 ± 5.5 to 94.3 ± 2.3%
by 10 minutes, which was maintained at 4 hours in 10/14 patients. The four in
whom saturations fell had PEEP levels below 10 cm H2O. The systolic blood
pressure decreased during the 20 second inflation in some patients, mean change of
6.9 mm Hg, which reversed rapidly following release of the maneuver in all
patients. No barotrauma was noted in any patient at 24 hour followup.

4. Pelosi, et al10 studied the effect of three consecutive 'sigh' breaths (one with
plateau pressure of 45 cm H2O but of normal duration) in 10 adults with ARDS.
After 1 hour of 3 sigh breaths per minute, end-expiratory lung volume (measured by
He dilution) increased from 1.49±0.58 to 1.91±0.67 L, and an increase in PaO2 from
92.8±18.6 to 137.6±23.9 mm Hg, compared with the same ventilator settings without
sigh breaths. Lung elastance and ventilation also increased. No adverse effects
were noted.

5. Toth, et al studied the cardiac and respiratory changes which occur in SI (40 cm
H2O for 40 seconds) in 18 adults with ARDS. The PaO2 increased from
pre-recruiting maneuver to following the 60 minute followup period (203±108 vs.
322±101 mm Hg, p < .001). Cardiac index (CI) and the intrathoracic blood volume
(ITBV) decreased following the recruiting maneuver (CI, 3.90±1.04 vs. 3.62±0.91
L/min/m2, p < .05; ITBVI, 832±205 vs. 795±188 mL/m2, p < .05). There was no
correlation with CI and mean arterial pressure, and no significant changes
occurred in mean arterial blood pressure.

6. In perhaps the largest study of sustained inflations in the protective ventilation
era, Meade, et al14 studied 983 adults with ARDS utilizing lung protective
strategies (tidal volumes 6 mL/kg) in both groups. The experimental group
utilized SI recruitment maneuvers (40 cm H2O for 40 seconds), higher levels of
PEEP (14.6±3.4 in the so-called 'lung open ventilation' group versus 9.8±2.7 in
the control group), and higher plateau pressures (30.2±6.3 versus 24.9±5.1 cm H2O)
than the control group, which did not utilize recruitment maneuvers. While there
was no difference in all-cause mortality, the experimental group had lower rates
of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54), death with refractory hypoxemia
(4.2% vs 8.9%; RR, 0.56), and less frequent use of escalated therapies (defined as
high frequency ventilation, inhaled nitric oxide, jet ventilation, or
extra-corporeal support) (5.1% vs 9.3%; RR, 0.6). This lends credence to the
notion that effective recruitment of children early in acute lung injury may avert
escalation of therapy and decrease the mortality due to severe hypoxia.

2. Pressure control ventilation (PCV) recruitment maneuver In contrast to a SI,
ventilating patients with increased plateau pressures and increased PEEP levels has
also been used as a recruiting maneuver. In this case, the patient is temporarily
placed on higher ventilator pressures than would be used to ventilate a patient
otherwise. A combination of PEEP and plateau pressures helps to recruit atelectatic
alveoli. Pressure control ventilation is the mode of choice in such patients because
in it the plateau pressure is set, and therefore kept constant (in contrast to volume
controlled ventilation). Thus, a known plateau pressure (which participates in lung
recruitment) is delivered. Following are the salient studies utilizing a PCV
recruitment maneuver. ? Athanasios "TLC maneuver" in anesthetized children? Small study
treating intraoperative atelectisis.

1. Borges, Amato, et al6 have performed the most convincing and complete study of the
maximal recruitment maneuver to date. In it, they studied 26 adults early in the
course of ARDS comparing the open lung approach (including SI of 40 cm H2O for 40
seconds, followed by PEEP set at Pflex + 2 cm H2O, described below) with the
maximal recruitment strategy, performed in sequence. Maximal recruitment was
defined as a PaO2 plus PaCO2 exceeding 400 mm Hg, indicative of minimal
intrapulmonary shunting. The strategy included pressure controlled ventilation of
15 cm H2O, with PEEP increased in 5 cm H2O increments every 5 minutes (maximum
PEEP 45 cm H2O) until maximal recruitment was achieved. Maximal recruitment was
achieved in 24/26 patients, two thirds of which were achieved by a PEEP of 30 cm
H2O. Utilizing a PEEP titration to maintain lung recruitment (see below), PaO2
remained above 400 (lungs fully recruited) in all patients at 6 hours. The
procedure was tolerated hemodynamically in all patients and the long-term
incidence of barotrauma in study patients (7.7%) was lower than the recognized
incidence in ARDSNet studies (10-11%)8.

2. Crotti, et al5 studied five adults with ALI/ARDS with varying plauteau pressures
(10, 15, 20, 30, 35, 40, 45 cm H2O) and PEEP levels (5, 10, 15, 20 cm H2O).
End-inspiratory and end-expiratory thoracic CT imaging was obtained with each
combination of plateau pressure and PEEP. Percentage of lung recruited (as
determined radiographically) increased in a nearly linear fashion with increasing
plateau pressures (Figure 1). The maximal opening frequency occurred at 20 cm
H2O, suggesting that plateau pressures exceeding 20 cm H2O would be most
beneficial in lung recruitment. No measures of gas exchange or adverse events
were studied.

3. Foti, et al15 compared changes in oxygenation and end-expiratory lung volumes at
increasing PEEP levels with superimposed volume controlled ventilation versus a
sustained inflation maneuver in 15 adults with ARDS. Although recruitment was
variable (due to the use of VCV, hence variable plateau pressures), he found that
maximal increase in oxygenation occurred at high sustained levels of PEEP (mean 16
cm H2O for 30 minutes) when compared with 30 second recruitment maneuvers and low
PEEP (mean of 9 cm H2O). The PEEP/plateau protocol was not associated with any
hemodynamic alterations, as with the sustained inflation maneuver.

4. Villagra, et al, studied a recruiting maneuver utilizing 2 minutes of ventilation
using pressure-controlled ventilation (PCV) in 18 adults with early ARDS. For the
RM, PEEP was set 3 cm H2O above the upper inflection point of the PV curve, and
peak pressures set to 50. Importantly, RM peak pressures did not differ
significantly from baseline ventilation (43.6±7.6 pre-RM, 47±4.5 during RM, and
42.8±7.1 cm H2O post-RM), although PEEP did (14±1.3 pre-RM vs 30±4.9 cm H2O). The
investigators did not find a significant difference in PaO2 following the
recruiting maneuver (127±63 pre-RM, 162±108 during, and 149±85 cm H2O post-RM).
This finding implies several important findings regarding lung recruitment.
First, the peak pressure represents a significant determinant in lung recruitment.
By contrast, Borges, et al were able to fully recruit all 18 ARDS patients by
using driving pressures differed significantly from pre-RM in the maximal
recruitment phase (50-60 cm H2O during recruitment vs 30 cm H2O at baseline).
Further, the recruiting maneuver utilized here was only 2 minutes, versus the
incremental titration utilized by Borges which lasted 4 minutes in each phase.
While not systematically studied, the lack of significant improvement in PaO2
post-RM found in this study suggests that recruitment utilizing PCV may be a
function of time and peak pressures utilized in the RM.

5. Medoff,3 et al presented a single patient with refractory hypoxemia. Management
included repeated sustained inflations with PEEP set just above Pflex based on the
PV curve. A recruiting maneuver including 20 cm H2O of PEEP and 40 cm H2O
distending pressure for 2 minutes was performed. The patient exhibited marked
improvement in oxygenation and near-complete recruitment of the lung by CT scan
(see Figure 2).

6. While all of the aforementioned studies achieved successful recruitment,
Gattinoni, et al11 studied 68 adults with late ARDS (5±6 days ventilation at
enrollment) who failed to successfully recruit. Recruitment maneuvers included
pressure-controlled ventilation with peak pressure of 45 cm H2O, PEEP of 5 cm H2O,
and respiratory rate of 10. PEEP levels were subsequently applied in random
order, between 5 and 15 cm H2O. He found that study patients had only 13±11%
recruitable lung by CT scan. Amongst all patients, he found that 24% of lung
tissue was non-recruitable, even at airway pressures of 45 cm H2O. No markers of
gas exchange were measured.

It is important to note three aspects of this study which are likely responsible for the
excessively high percentage of non-recruitable lung, in contrast with the highly successful
recruitment strategy outlined by Borges, et al. First, Borges studied patients early in the
ARDS course (median, 2 days) while Gattinoni studied late ARDS. Second, Borges utilized
peak pressures as high as 60 cm H2O, while Gattinoni utilized pressures up to 45 cm H2O.
Finally, Gattinoni did not practice a PEEP titration, but lowered PEEP to 5 cm H2O following
recruitment maneuvers. Thus, Gattinoni's study highlights the importance of high peak
pressures in lung recruitment, of recruiting early in ARDS, and of a decremental PEEP
titration to maintain lung recruitment.

C. Strategies of Maintaining Recruitment The application of positive end-expiratory pressure
is known to prevent repetitive derecruitment-recruitment stresses on lung tissue. In an
animal model of acute lung injury, Farias showed histologic and biochemical evidence of
atelectotrauma is averted when PEEP is applied following lung recruitment7. The two
principal strategies to prevent derecruitment following a recruitment maneuver include the
open lung approach and decremental PEEP titration.

1. Open Lung Approach In the open lung approach, PEEP is set just above the lower
inflection point (also known as Pflex) of the patient's pressure-volume curve. This
theoretically prevents the PEEP from decreasing below the zone of underdistension.

1. In a second part of the study mentioned above, Richard, et al4 also studied the
effect of increasing PEEP relative to the measured LIP (LIP + 4 cm H2O, no SI)
compared to PEEP set at the lower inflection point following SI. In 10 adults
ventilated with low-tidal volume ventilation, measured lung volumes were 175±108
at PEEPLIP versus 332±91 ml at PEEPLIP+4. This increase was even more notable in
patients ventilated with high tidal volumes (10 mL/kg), demonstrating the role of
plateau pressures (in addition to PEEP) in alveolar recruitment (see Figure 3).

2. Amato, et al16 studied the effects of a 'protective ventilation strategy' in 53
patients with ARDS. The protective ventilation group received recruitment
maneuvers via sustained inflation (35-40 cm H2O for 40 seconds) followed by PEEP
set at LIP + 2 cm H2O. The control group received a PEEP titrated to saturations,
no recruiting maneuvers. The protective ventilation group had a dramatic decrease
in 28 day all-cause mortality (38% vs 71%, p<0.001). However, the control group
also received high tidal volume ventilation (12 mL/kg), later proven to be a
significant determinant in ARDS mortality.8 Therefore, the contribution of RM and
open lung approach to the improved mortality of this study, if any, is difficult
to conclude.

2. Decremental PEEP Titration In a decremental PEEP titration, following a recruiting
maneuver, the PEEP is set at a high level, often between 20 and 26 cm H2O. PEEP is
decreased incrementally, and markers of lung inflation (e.g. gas exchange or measured
lung volume) are followed. When evidence of atelectasis occurs, PEEP is held at or
just above this level, often termed 'optimal PEEP.'

1. Borges, Amato, et al6 describe a PEEP titration following a maximal recruitment
protocol and compare it to the open lung approach (PEEP set at Pflex + 2 cm H2O).
Following a maximal recruitment strategy (described above), PEEP was set at 25 cm
H2O and decreased by 2 cm H2O every 4 minutes until PaO2 + PaCO2 < 380 mm Hg, then
increased by 2 cm H2O (optimal PEEP, mean 20±5 cm H2O). Using this strategy, PaO2
was sustained at levels above 400 mm Hg at 30 minute followup in all 24 patients
(see Figure 4, top), and above 450 in the 16 patients followed for 6 hours. This
correlated with a percent mass of collapsed tissue as measured by CT scan of <5%
at end of PEEP titration and at 30 minute followup (see Figure 4, bottom).

2. Toth, et al17 described a decremental PEEP titration following a SI recruiting
maneuver. Following SI at 40 cm H2O for 40 seconds, PEEP was set at 26 cm H2O,
then decreased by 2 cm H2O every 4 minutes until the PaO2 decreased by >10% of its
peak value. The PEEP 2 cm H2O above this was defined as optimal PEEP. Optimal
PEEP was found to actually be lower than the patients' baseline PEEP (prior to
protocol initiation, 17±3 vs 15±4 cm H2O). The PaO2 following the recruiting
maneuver (203±108 at baseline PEEP vs 328±132 cm H2O) sustained at the 30 minute
followup period (266±121 cm H2O, p<0.05 compared to baseline).

D. Estimating Lung Volumes Currently, the ability to determine whether a patient is at,
below or above their ideal functional residual capacity is deduced from surrogate
measurements, including lung appearance of the chest radiograph, vital sign trends
(particularly oxygenation), and pressure-volume (P-V) curves generated by modern
ventilators. In this study, we will utilize an established method of determining lung
volume (MBNW) to study lung volumes.

1. Pressure-Volume Curves The pressure-volume curve represents the continual relationship
between changes in pressure and changes in volume of the lung. The slope of the line
represents the compliance of the lung. In Figure 5, note the three lines which
comprise the inspiratory limb (lower curve). The leftmost line represents
noncompliant, atelectatic lung. The point at which the slope changes is known as the
lower infection point, also known as Pflex. In the open lung approach (discussed
later), PEEP is set to a pressure just above the lower inflection point.
Physiologically, it is hypothesized that this is the point at which all atelectatic
segments of lung are recruited, and that disallowing ventilator pressures from dropping
below this at any point (by setting PEEP above this level) minimizes atelectasis. The
point which distinguishes the second change in slope of the line (becoming flat again)
is known as the upper inflection point (UIP). Pressures above this point represent
overdistended, noncompliant alveoli, and thus this point represents the pressure at
which the compliance of the lung decreases dramatically. In this protocol, the PV
curve will be measured for each patient and the UIP utilized as the ceiling pressure at
any point in the protocol. In this way, we will recruit compliant areas of the lung
without the risks of overdistension.

2. Nitrogen Multiple Breath Washout Technique (MBNW)

MBNW has been utilized in a number of clinical studies, and is considered to be a gold
standard in the measurement of lung volume18-21. Currently, the most accurate way to
measure the volume of the lung is through dilution of a known amount of a gas with low
solubility be rebreathing in a closed system. The changes in concentration with
sequential breaths allow a calculation of the volume of distribution of the gas. One
gas which has been utilized for this purpose is nitrogen22, appealing due to its
ubiquitous presence in the environment. Measurement of nitrogen gas concentrations,
however, is available only using gas chromatography or mass spectrometry, neither of
which is clinically practical. Recently, a technique has been validated by which the
partial pressure of nitrogen is calculated as the residual of partial pressures of
oxygen gas, carbon dioxide gas and nitrogen gas, which together comprise the only three
important gases in a ventilator circuit. The former two gases are readily measured in
a ventilator circuit in real time, but of course vary widely with the metabolic state
of the patient. Stenqvist has developed the NMBW technique to calculate FRC using the
changes in exhaled O2 and CO2, manipulating inspired oxygen concentration to alter
fraction of inspired nitrogen23. FRC is calculated as follows:

FiN2 = 1-FiO2 (set by ventilator) FeO2 = 1-FeO2 (measured)-FeCO2 (measured)

Inspired and expired alveolar tidal volumes are calculated using O2 consumption (VO2)
and CO2 production (VCO2) as calculated by indirect calorimetry24:

Volumes of inspired and expired nitrogen gas associated with a single breath are
calculated from end-tidal nitrogen content (EtN2, inferred from measured expired CO2
and oxygen content), inspired nitrogen fraction (FiN2) and inspiratory and expiratory
alveolar tidal volume as follows:

Before making the incremental 10% change in FiN2 via manipulating FiO2, baseline values
for VO2, VCO2 and ETN2 are made. VO2 and VCO2 are assumed to be constant throughout
the measurement. The FiN2 is then manipulated, and FRC estimated as follows:

Measurement of FRC using this methodology in a lung model of known oxygen consumption
and lung volumes23 revealed excellent precision (mean FRC 103 5%) even when utilizing
incremental changes in FiO2 from 0.9 to 1.0. Precision in adult patients with
respiratory insufficiency revealed excellent precision amongst measurements.

3. Electrical Impedance Tomography (EIT) Electrical impedance tomography capitalizes on
changes in impendence in air-filled versus tissue-filled spaces to characterize and
quantify regional distribution of lung volume at the bedside. Significant work has
been done in the past decade to validate the technology in animals25 and in humans26,
27. The technology utilizes a series of 16 electrodes placed across the patient's
chest (Figure 6). As small currents are passed between the electrodes, impedance is
measured between and amongst the series. Through a complex interrogation and
manipulation of these impedance values, a two-dimensional image is formed (Figure 7),
and has been shown to correlate with clinical and radiographic changes in patients27.
In ten mechanically ventilated adults with ARDS, end-expiratory lung volume as
determined by nitrogen washout correlated well with end-expiratory lung impedance with
an r2 of 0.95.26 The ability to estimate lung volume non-invasively and in real time
may significantly improve outcomes in patients with lung injury. Specifically, the
ability to determine a patient's ideal functional residual capacity and ventilate them
towards that goal may improve oxygen delivery by maximizing pulmonary compliance and
minimizing pulmonary vascular resistance. This study seeks to utilize varying levels
of PEEP to alter end-expiratory volume, using EIT and other surrogate measures to
confirm efficacy, measuring oxygenation and shunt fraction as the clinical end points.
Should this study demonstrate the ability to effectively recruit lung and minimize
shunt fractions using an aggressive PEEP strategy, further studies of clinical benefit
from this will be warranted.

4. Exhaled Breath Condensate (as measure of lung health) There is a growing body of
evidence regarding changes in airway lining fluid (ALF) pH in acute and chronic
respiratory diseases that are characterized, at least in part, by inflammation. It has
been demonstrated that the pH of ALF is low (acidic) in multiple pulmonary inflammatory
diseases including asthma28, cystic fibrosis29, pneumonia, and ARDS30-32, and that this
pH can be detected continuously, safely and non-invasively in exhaled breath condensate
(EBC)33. The pH of EBC may be a safe, non-invasive screening tool for progression of
ARDS, and of lung recruitment. It has anecdotally been shown to predict respiratory
failure and impending respiratory infection (unpublished data). As seen in Figure 4
(left), the EBC pH is a marker exhibiting rapid turnover and thus may be valuable for
real-time monitoring of lung pathology.

Continuous exhaled breath condensate pH collection and assay system (ALFA monitor,
Respiratory Research, Inc., Austin, Texas) consists of a condenser attached to the
expiratory limb of the ventilator. Exhaled breath condensate is collected continuously from
the expiratory port, condensed in a cooling chamber, CO2 removed, and collected in an
inferior chamber where pH is continuously read. This yields a continuous, responsive
measure from ventilated patients, which (1) takes samples from an exhaust port on the
outside of the ventilator circuit, and (2) adds no measurable resistance to the ventilator
circuit. The measurement of EBC in patients with lung injury may serve as an early marker
of derecruitment.

II. Study Objectives Specific Aim 1: To demonstrate the efficacy of the a maximal
recruitment strategy to increase lung volumes and improve oxygenation in children with acute
lung injury, utilizing multiple breath nitrogen washout (MBNW) and electrical impedance
tomography (EIT) as measures of lung volume. (Hypothesis: Lung volumes and oxygenation
will increase following the maximal recruitment protocol as compared to those during
'baseline ventilation' or the 'open lung approach.') Specific Aim 2: To compare lung
volumes as measured by MBNW and EIT at varying end-expiratory lung volumes. (Hypothesis:
Lung volumes as measured by MBNW will correlate with those obtained by EIT.)

Inclusion Criteria:

All intubated and mechanically ventilated patients on the Medical-Surgical Intensive Care
Unit will be screened for the following inclusion criteria:

1. Age: 44 weeks post conceptual age to 18 years

2. Acute Lung Injury (ALI): American European Consensus Committee definition of ALI40

1. PaO2/FiO2<300 on ABG within past 6 hours,

2. Acute onset of bilateral infiltrates on chest radiograph, and

3. No evidence of left atrial hypertension

3. Sedation: Must be receiving neuromuscular blockade or demonstrating apnea due to
sedation

4. Arterial line must be present

5. Conventional mechanical ventilation

6. Current PEEP levels between 5 and 15 cm H2O

Exclusion Criteria:

1. Meets the above criteria for ALI for > 72 hours

2. Active hemodynamic instability

3. Prematurity (birth at post-conceptual age <37 weeks)

4. Clinically recognized airways disease (including viral bronchiolitis)

5. Uncuffed endotracheal tube in place

6. Congenital heart disease

7. Hemodynamically significant heart disease

8. Congenital diaphragmatic hernia

9. Recent (past 2 months) history of intrathoracic instrumentation (e.g., orthopedic
instrumentation, cardiac pacemaker, thoracostomy)

10. Pulmonary fibrosis

11. Restrictive lung disease (other than acute lung injury/ARDS)

12. Cystic fibrosis

13. Severe pulmonary hypertension

14. Severe brain injury with no intracranial pressure monitor or external ventricular
drain in place

15. Extra-corporeal life support