Efficacy and Safety of a Lung Recruitment Protocol in Children With Acute Lung Injury
Efficacy and Safety of a Lung Recruitment Protocol in Children With Acute Lung Injury
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), which results in impaired gas exchange and induces an inflammatory
 cascade. Currently, there is no clinical practice guideline in our intensive care unit
 regarding lung recruitment strategies for children with lung injury. While many studies have
 demonstrated efficacy (ability to open the lung) and safety of recruitment maneuvers in
 adults, no such studies have been performed in children.

 The primary purpose of this study is therefore to demonstrate the safety and efficacy of a
 recruitment protocol designed to maximally recruit collapsed lung in children with acute lung
 injury. Each study patient will follow a recruitment protocol (see Appendix 2). Two
 'controls' will be utilized in this study: baseline ventilation (no recruitment maneuver) and
 the open lung approach (a sustained inflation followed by increased PEEP). Efficacy will be
 defined as an improvement in lung volume (as measured by nitrogen washout and electrical
 impedance tomography), and by an improvement in measured arterial partial pressure of oxygen.
 Safety will be defined as the incidence of barotrauma and hemodynamic consequences which
 occur during the protocol.

 A secondary purpose of this study will be to further validate electrical impedance tomography
 (EIT) as a non-invasive tool describing the lung parenchyma by comparing it to an accepted
 standard method of measuring lung volumes, the multiple breath nitrogen washout technique.
 Validation of EIT would allow clinicians to have a non-invasive image of a patient's lungs
 without the risks imposed by radiography.

 The information we learn will be instrumental in defining an optimal strategy for lung
 recruitment in children with 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 ALI

 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