Recent data from large trials of high-frequency high frequency oscillation (HFO) without a cuff leak vs, lung-protective conventional ventialtion (CMV) failed to show any HFO-related benefit with respect to outcome. A possible explanation is that HFO increases the probability of right ventricular dysfunction due to the combination of high mean airway pressures (mPaws) and hypercapnia. In contrast, available preliminary data on low-frequency HFO-tracheal gas insufflation (TGI) with cuff leak vs. CMV are suggestive of an HFO-TGI related benefit. Low-frequency HFO-TGI with a cuff leak is associated with relatively low mean tracheal pressures and adequate control of PaCO2. Thus, the investigators intend to test the hypothesis that low frequency HFO +/- TGI with a cuff leak is associated with better right ventricular function relative to high-frequency HFO without a cuff leak.

Rationale of the study Acute Respiratory Distress Syndrome (ARDS) is an acute inflammatory state of the pulmonary parenchyma that causes hypoxemia, atelectasis, pulmonary congestion, and reduction in pulmonary compliance. Mechanical ventilation is actually life-saving, but it may traumatize the lungs (e.g. volutrauma, barotrauma, atelectrauma, and biotrauma). The use of low tidal volumes and high positive end-expiratory pressure (PEEP), aims at attenuating ventilator-associated lung injury. However, ARDS mortality still remains high. High frequency oscillation (HFO) is an alternative ventilatory technique that employs very low tidal volumes (1-4 ml/kg) administered at high frequencies (3-15 Hz). Prior observational studies have reported improvements in oxygenation, whereas recent two-center data on severe ARDS suggest a survival benefit from the intermittent, combined use of low-frequency HFO with a cuff leak, Recruitment maneuvers (RMs), and tracheal gas insufflation (TGI). The addition of TGI improves oxygenation and CO2 elimination; however, it is still unclear whether it affects survival. Two recently published multicenter studies showed either neutral (10) or negative results (11) with respect to survival when high frequency HFO without a cuff leak was used in the treatment of early ARDS. However, these negative results may be partly due to right ventricular overload/dysfunction/failure caused by the combination of high intrathoracic pressures and hypercapnia, with consequent hemodynamic instability and increased need of inotropic/vasopressor support. Accordingly, the investigators hypothesize that a different HFO strategy [employing a combination of a low frequency and a cuff leak - which augments CO2 elimination and is associated with relatively low mean tracheal pressures - could lead to different results.

A high intrathoracic pressure may impede venous return and increase pulmonary vascular resistance. This concurrent right ventricular preload reduction and afterload increase might cause right ventricular dysfunction/failure. On the other hand, the placement of a cuff leak results in a lower (by approx. 5-6 cmH2O) mean tracheal pressure relative to the set HFO-ventilator mean airway pressure (mPaw), with consequent unloading of the right ventricle. In addition, further unloading of the right ventricle can be expected through the combined use of a cuff leak, TGI, and a high HFO bias flow; these measures improve PaCO2 control and may prevent excessive, hypercapnia-induced increases in pulmonary vascular resistance. Right ventricular function can be assessed by transesophageal echocardiography (TEE) as previously described. Right ventricular dysfunction and associated dilatation may cause cardiac output reduction and coronary hypoperfusion; the latter may further compromise right ventricular performance and contribute to right ventricular failure.

The main goal of the present study is to document and compare the effect of lung protective conventional mechanical ventilation (CMV) and of different HFO strategies (already clinically tested in trials with conflicting results) on right ventricular performance as determined by TEE. More specifically, we intend to compare high-PEEP, lung protective CMV with a "high" mPaw/no cuff leak, high-frequency HFO strategy, and a "high" mPaw with cuff leak, "low" frequency HFO strategy with and without TGI.

Methods METHODS Eligible patients (relevant criteria provided below) with early and severe ARDS will be enrolled after the obtainment of informed, written, next-of-kin consent, as well as attending physician's non-written consent..

Patient monitoring will include electrocardiographic lead II, intra-arterial pressure (+/- cardiac index with PICCO plus, Pulsion Medical Systems, Munich, Germany)], and peripheral oxygen saturation (SaO2). Anesthesia will be maintained with midazolam and/or propofol, and fentanyl or remifentanil. Nrutomuscular blockade will be accomplished with cisatracurium, which will be used in concordance with current recommendations and as part of the attending physician-prescribed medical treatment. During the study period, all patients will be receiving a continuous infusion of cisatracurium.

CMV strategy Eligible study participants will have received at least 60 min of lung protective CMV with the following combinations of FiO2/PEEP: 0.5/10-12 cm H2O, 0.6/14-16 cm H2O, 0.7/14-16 cm H2O, 0.8/14-16 cm H2O, 0.9/16-18 cm H2O, 1.0/20-24 cmH2O. These combinations constitute "general" recommendations and further PEEP titrations of =< 4 cm H2O by attending physicians to the "best" combination of the patients' gas exchange and hemodynamic will be considered as acceptable. A high-PEEP-associated survival benefit has been recently documented. Whenever oxygenation deteriorates, PEEP will be increased first, followed by an increase in FiO2, while targeting "concordance" with the aforementioned FiO2/PEEP combinations.

Tidal volume will be within 5.5-7.5 mL/Kg predicted body weight. The maximal plateau pressure limit will be 40 cmH2O, and target plateau pressure will be ≤32 cmH2O; rationale: as in the study of Meade et al , a higher plateau pressure will be tolerated to allow for the use of a higher PEEP level. When plateau pressure exceeds 32 cmH2O for >15 min, the following adjustments will be conducted: tidal volume reduction up to 4.0 mL/kg predicted body weight, respiratory rate increase up to 35/min, and PEEP reduction by ≥2 cmH2O. These adjustments will have to concurrently result in the achievement of the below-provided gas-exchange targets.

The respiratory rate will be titrated to a pHa of 7.20-7.45. The inspiratory-to-expiratory time (Ι:Ε) ratio will be ≤1/2. The oxygenation target will be SaO2=90-95%, and/or PaO2=60-80 mmHg. At pHa<7.20, breathing circuit deadspace will be minimized by replacing the routinely used catheter mount by a short, low-volume angular connector, the tidal volume will be increased up to 8.0 mL/kg predicted body weight, and respiratory rate will be increased up to 35/min. If these measures fail, the criterion of "poor control of pHa/PaCO2," and the use of a bicarbonate infusion will be permitted. An additional option will be extracorporeal CO2 removal.

Algorithm of RMs and PEEP/FiO2

1. RM - Continuous positive airway pressure of 40-45 cmH2O for 40 sec, at an FiO2 of 1.0) and titration of PEEP and FiO2 so that SaO2=90-95%, or PaO2=60-80 mmHg (RMs may be repeated twice daily, once every 5 hours)
2. Reduction in FiO2 always precedes reduction in PEEP.
3. At FiO2=0.5 and PEEP<8 cmH2O - Weaning trial.
4. RMs may be administered for up to 5 days following the onset of the ARDS

HFO-RMs strategy

Previously published recommendations regarding HFO use (Sensormedics 3100B ventilator, Sensormedics, Yorba Linda, CA, USA) include the following steps:

1. Sufficient level of deep sedation/anesthesia for the abolishment of respiratory muscles activity, with or without neuromuscular blockade, so that patient-ventilator dyssynchrony is avoided.
2. Confirmation of endotracheal tube patency and placement of the tube at 3-4 cm above carina.
3. RMs: immediately after patient-oscillator connection, an RM will be performed (increase in the circuit pressure to 45 cmH2O for 40 sec with the oscillator's piston off). The RMs will be repeated just prior to changes in HFO frequency or just prior to/just after the initiation/termination of TGI.
4. FiO2 will initially be set at 1.0 and then reduced (over 10-15 min) to the FiO2 of the preceding CMV, provided that SaO2 is maintained >90%.
5. Bias flow will be set at 60 L/min to improve CO2 clearance from the breathing circuit.
6. I:E ratio will be maintained at 1:2.
7. According to the methods and results of preceding studies of the investigators, TGI will be equal to 50% of the preceding CMV minute ventilation.
8. The initial HFO mPaw will exceed the mPaw of the preceding CΜV by 8-10 cm H2O and will be titrated (by ±3 cmH2O) to the best oxygenation response (predicted to correspond to a "target" SaO2 of >= 95%) during a 60-min period of standard, low frequency HFO with cuff leak. The aforementioned period will precede the below-described 180-min period of HFO strategy testing.
9. Initial oscillation frequency will be randomly set at either at 3.5-4 Hz or at 7 Hz. The low frequency setting will be combined with a 3-5 cmH2O cuff leak and TGI for 60 min followed by "no-TGI" for another 60 min in random order. The high frequency setting will not be combined with either a cuff leak or TGI and will be maintained for an additional 60 min. Oscillatory pressure amplitude (ΔP) will be set at 90 cmH2O.

TEE measurements

The following parameters will be determined during baseline CMV:

Right ventricular diastolic area, left ventricular diastolic area, and Eccentricity Index. Assessment of coronary blood flow in the right main coronary artery and the left anterior descendant branch of the left main coronary artery (Note: coronary artery blood flow measurements proved technically difficult and time-consuming and were thus removed from the study protocol). The same measurements will be repeated at 120, 180, and 240 min after HFO initiation, and at 60 min following return to CMV. At the same time points, we will determine gas exchange, and hemodynamics including cardiac output with PICCO plus. Lastly, respiratory mechanics will be assessed with rapid end-expiratory/end-inspiratory airway occlusion during CMV.

Rescue oxygenation Rescue oxygenation methodology may include low-frequency HFO-TGI with cuff leak, prone positioning, inhaled nitric oxide, and extracorporeal membrane oxygenation. The duration of a rescue oxygenation session will be at least 10 hours with allowance for an unlimited extension if PaO2<60 mmHg. Rescue initiation criterion: PaO2<60 mmHg for more than 30 min at FiO2=1.0 during the high-PEEP, lung protective CMV, in the absence of any reversible cardio-respiratory pathology and/or ventilator malfunction.

Patient follow up Physiological variables (hemodynamics gas-exchange, and respiratory mechanics) and medication will be recorded within 2 hours before study enrollment and at 9 a.m. of days 1-10 following study enrollment. Organ dysfunction according to the Sequential Organ Dysfunction Assessment score and clinical course complications will be documented until day 60 post-enrollment. Lastly, the final outcome (i.e. survival to hospital discharge or in-hospital death) will also be recorded.

POTENTIAL RISKS OF INVESTIGATIONAL INTERVENTIONS AND THEIR PREVENTION. Potential risk: Barotrauma. Preventive measures: This potential risk is equally high during CMV or HFO. We also do not anticipate any notable clinical complications due to the use of high-frequency, high mPaw HFO without cuff leak, as its duration of use will not exceed the protocol-pre-specified time limit of 60 min.

POSSIBLE BENEFITS For the participating patient: possible increase in the probability of survival to hospital discharge if HFO-TGI is used as a rescue oxygenation method and detailed TEE evaluation of the cardiac function. For Medical Science: Possible improvement in the understanding of the interaction among ventilatory strategy, heart, and lungs.

Inclusion Criteria:

Acute Respiratory Distress Syndrome (ARDS) according to the Berlin Definition Onset of ARDS within the 72 hours preceding study enrollment PaO2/FiO2 of less than 150 mmHg while ventilated with a positive end-expiratory pressure of at least 10 cmH2O Body weight of more than 40 Kg Age 18-75 years

Exclusion Criteria:

Severe air leak (more than one chest tubes per hemithorax with persistent air leak for more than 72 hours) Systolic blood pressure lower than 90 mmHg, despite maximum support with fluids and vasopressor drugs Significant heart disease Severe chronic obstructive pulmonary disease or asthma Intracranial hypertension Chronic interstitial lung disease with bilateral lung infiltrates Lung biopsy or incision during the current admission Previous lung transplantation or bone marrow transplantation Pregnancy