High Frequency Oscillatory Ventilation for Acute Respiratory Distress Syndrome (ARDS)
High Frequency Oscillatory Ventilation for Acute Respiratory Distress Syndrome (ARDS)
Based on recent two-center results (Eur Respir J. 2011 Sep 1. [Epub ahead of print] PMID:
 21885390) we hypothesized that intermittent High-frequency oscillation (HFO) combined with
 Recruitment Maneuvers (RMs) may beneficially affect the pathophysiology and survival of
 patients with moderate-to-severe Acute Respiratory Distress Syndrome (ARDS).

 Design: Randomized Controlled Trial. Intervention: Briefly, the HFO-RMs strategy of the
 intervention (HFO-RMs) group will comprise RMs (3/day) and an initial HFO session of 96 hours
 (HFO session can be interrupted before the 96-hour time point only if PaO2/FiO2 rises to >200
 mmHg for >12 hours), followed by return to lung protective conventional mechanical
 ventilation (CMV) according to pre-specified oxygenation criteria. Within days 1-10
 postrandomization, patients will be returned to HFO upon recurrence of their
 moderate-to-severe oxygenation disturbance. Patients of the control (CMV) group will receive
 lung protective CMV.
BACKGROUND AND RATIONALE Recent two-center results (1) support a beneficial effect of
 combined high-frequency oscillation (HFO), recruitment maneuvers (RMs) and tracheal gas
 insufflation (TGI) on the survival of patients with severe acute respiratory distress
 syndrome (ARDS). The addition of TGI to HFO improves gas-exchange (1-4); however, its value
 with respect to outcome still remains uncertain (1). TGI is likely useful in patients with
 very severe oxygenation disturbances and/or poor tolerance to hypercapnia (2).

 The main goals of the present study are 1) The determination of the effect of the
 intermittent, combined use of HFO and RMs (HFO-RMs - intervention group) on the survival as
 compared to the best possible strategy of lung-protective conventional mechanical ventilation
 (CMV - control group); and 2) the elucidation of the mechanism of action of HFO on
 respiratory function and the ARDS-related inflammatory response.

 The consecutive hypotheses supporting the conduct of the present trial can be summarized as
 follows:

 The use of HFO + RMs will likely augment lung recruitment, with consequent improvements in
 oxygenation and lung compliance The HFO-related, physiological benefits will likely be
 maintained during the subsequent CMV, if an adequate positive end-expiratory pressure (PEEP)
 level is used (1).

 Therefore, the following sequence of events is expected from the intermittent use of HFO-RMs:

 -  Lung Recruitment & Compliance →

 -  Ventilation pressures during the subsequent CMV (as compared to pre-HFO CMV)→

 -  Risk of ventilator-associated lung injury →

 -  ARDS-related inflammatory response →

 -  ARDS-related organ or system failure(s) →

 -  Survival

 These hypotheses are consistent with preceding results on 125 patients (1). The present
 HFO-RMs protocol will be simplified relative to that of our previous study, in order to
 improve its generalized applicability. The use of HFO-TGI will be optional and limited to 1)
 rescue oxygenation procedures for both the HFO-RMs and CMV group; and 2) certain patients of
 the HFO-RMs-group with "very severe oxygenation disturbances" (see below for definition), or
 "poor control" of arterial pH (pHa)/PaCO2 (see below). The frequency of HFO-TGI use will be
 compared between the 2 study groups after study completion.

 METHODS Patients The study protocol has received Institutional Review Board Approval. An
 Information Sheet detailing the potential benefits and risks of study participation will be
 provided to the next-of-kin of eligible patients. Following discussion of the study with one
 of the investigators, a written, next-of-kin consent for study participation will be
 requested. As soon as clinically feasible, patients will be informed of the study and of
 their right to withdraw.

 Study participants must fulfill the eligibility criteria presented in the dedicated section.
 Continuous patient monitoring will include electrocardiographic lead II, inra-arterial
 pressure with/without cardiac index (PICCO plus, Pulsion Medical Systems, Munich, Germany),
 and peripheral oxygen saturation (SaO2). Anesthesia will be maintained with continuous
 infusions of midazolam or propofol and fentanyl or remifentanil. Neuromuscular blockade with
 cisatracurium will be used in concordance with standard recommendations (6), and as part of
 attending physician-prescribed medical treatment. During the first 48 hours post-enrollment,
 all patients will receive a continuous infusion of cisatracurium (7).

 Randomization Patient randomization will result in assignment to the control (CMV) group
 (which will receive treatment with CMV alone), or to the intervention (HFO-RMs) group [which
 will receive treatment with an extended HFO session of at least 96 hours (HFO session can be
 interrupted before the 96-hour time point only if PaO2/FiO2 rises to >200 mmHg for >12
 hours)], and whenever required, additional HFO sessions of at least 12-24 hours, interspersed
 with CMV as described below).

 For each participating center, a sequence of unique random numbers from 1 to 200 will be
 generated apriori with the Research Randomizer (www.randomizer.org). To achieve concealment
 until patient study entry, each random number will be marked on a piece of paper placed in an
 opaque envelope, which will be subsequently sealed. Envelopes will be prepared by the
 department's statistician, and will be externally labelled with the patient serial number.
 Envelopes will be opened following the patient serial number order after the obtainment of
 signed informed consent. Thus, on each consecutive study entry, an envelope will be opened
 and the random number it contains will be assigned to the patient as his/hers unique
 study-number. Patients with even and odd study-numbers will be allocated to the CMV and
 HFO-RMs group, respectively.

 CMV strategy Immediately after randomization, study participants will receive 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. Whenever oxygenation improves, FiO2 will
 be reduced first, followed by the reduction in PEEP according to the aforementioned FiO2/PEEP
 combinations. Whenever oxygenation deteriorates, PEEP will be increased first, followed by
 the increase in FiO2 according to the aforementioned FiO2/PEEP combinations. Rationale for
 the use of high PEEP: According to a recent meta-analysis (8), the use of PEEP levels
 comparable to those proposed by the present protocol may be associated with an improved
 survival.

 In patients with a body mass index of >27 kg/m2 and/or an urinary bladder pressure of ≥15
 mmHg, the positivity of end-expiratory transpulmonary pressure (PLend-exp) will be confirmed
 with the esophageal balloon technique (9,10), once daily for the first 10 days
 post-randomization; in case of a negative PLend-exp, the PEEP level will be increased so that
 PLend-exp becomes positive (10); rationale: obese patients and patients with increased
 intra-abdominal pressure are more likely to require higher PEEP levels for the prevention of
 expiratory derecruitment.

 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 (7); rationale: as in
 the study of Meade et al (11), 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 connecting the Y piece
 directly to the tracheal tube (7), 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. Additional options will include the use of TGI of 6-7 L/min, or extracorporeal CO2
 removal.

 In the CMV group, RMs (Continuous positive airway pressure of 45 cmH2O for 40 s at FiO2=1.0)
 will be used at a frequency of 3/day for the first 5 days post-randomization. RMs will start
 at 9:00 a.m. and will be repeated every 5 hours; this means that the second RM will be
 performed at 2:00 p.m., and the third RM at 7 p.m. If during an RM, SaO2 drops by 10%, or
 mean arterial pressure drops by 25%, the RM will be immediately aborted, and the next RM will
 be performed after at least 10 hours. If the first daily RM is aborted, then the second RM
 will be cancelled and the third RM will be administered. If the second daily RM is aborted,
 then the third daily RM will be cancelled. If the third daily RM of days 1, 2, 3, or 4 is
 aborted, the next RM will be conducted at 9:00 a.m. of the subsequent day. After day 6, there
 will be no protocolized use of RMs; rationale: as time from ARDS onset passes, the
 probability of RM-associated oxygenation improvement decreases and the risk of RM-related
 hypotension increases (12).

 HFO-RMs strategy In the HFO-RMs group, HFO sessions will be used during days 1-5
 post-randomization; rationale: in NCT00637507 HFO was used for ≤5 days in ~75% of the
 patients of the intervention group (1). The daily HFO sessions will start at 9 a.m. and last
 a minimum of 12 hours. The HFO-RMs strategy is described below.

 Recently published recommendations regarding HFO use (Sensormedics 3100B ventilator,
 Sensormedics, Yorba Linda, CA, USA) include the following steps (13).

 1. Sufficient level of sedation for the abolishment of respiratory muscles activity, with
 or without neuromuscular blockade; the latter will be mandatory during the first 48
 hours (7).

 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 45-50 cmH2O for 40 s with the oscillator's piston off).
 During days 1-5 post-randomization, RMs will be repeated every 5-6 hours. RM abort
 criteria will be the same as for the CMV group. In the HFO-RMs group, RMs will be used
 solely during HFO.

 4. FiO2 will initially be set at 1.0, and then adjusted according to protocol (see below).

 5. Bias flow will be set at 60 L/min; rationale: this maximal bias flow setting is expected
 to result in improved CO2 clearance from the HFO breathing circuit.

 6. Initial oscillation frequency will be 4 Hz, and will be titrated to a pHa of >7.20. The
 minimum value of oscillation frequency will be 3.5 Hz; rationale: our HFO experience
 suggests that the use of frequencies of <3.5 Hz are associated with increased risk of
 high-frequency ventilator malfunction.

 7. Oscillatory pressure amplitude (ΔP) will be initially set at 90 cmH2O and will be
 titrated according to a pHa of >7.20 (range=60-100 cm H2O).

 8. A tracheal tube cuff leak will be placed to facilitate CO2 elimination. The associated
 reduction in mean airway pressure (mPaw) of 4-5 cmH2O will be immediately reversed by
 using the corresponding control knob. Cuff pressure will be maintained at ≥20 cmH2O.

 9. If pHa<7.20, despite an oscillation frequency of 3.5 Hz and a maximal ΔP setting of 100
 cmH2O, the deadspace of the breathing circuit will be minimized by connecting the Y
 piece directly to the tracheal tube (7). If pHa still remains <7.20, the criterion of
 "poor control of pHa/PaCO2" will be fulfilled, and the use of a bicarbonate infusion
 will be permitted. As during CMV (see above), additional options will include the use of
 TGI of 6-7 L/min, or extracorporeal CO2 removal.

 10. The I:E ratio will be maintained at 1:2.

 11. mPaw adjustments will be as follows: Α] Initial mPaw=mPaw CMV + 10-13 (maximal
 allowable=45) cm H2O, Β] Within the next 2 hours: mPaw titrations of ±3 cm H2O to
 determine the "optimal mPaw setting" that achieves the highest PaO2 at FiO2=1.0, and C]
 Reduction of mPaw at a rate of 1-2 cmH2O/6 hours, with each downward titration being
 preceded by an RM.

 12. Patients will be returned to CMV after a maximum of 96 hours after HFO initiation,
 provided that a PaO2/FiO2 of >200 mmHg is achieved for >6 hours. Return to CMV before 96
 hours after HFO initiation will be allowed whenever PaO2/FiO2 rises of >200 mmHg will be
 achieved and maintained for >12 hours during HFO. Within days 5-10, patients will be
 returned to HFO whenever PaO2/FiO2 falls below 200 mmHg for >12 hours; the criterion of
 re-return to CMV will again be PaO2/FiO2 >200 mmHg for >12 hours or the end of day 10,
 provided that at this time point PaO2/FiO2 exceeds 100 mmHg; any subsequent use of HFO
 will be according to the below-presented protocol of "Rescue Oxygenation."

 13. TGI of 6-7 L/min will be permitted as an option if the patient fulfills the following
 criterion of "very severe oxygenation disturbance": During the pre-HFO CMV, the patient
 requires an FiO2 of 0.9-1.0 (and a PEEP level of ≥16 cmH2O) to maintain an SaO2 of
 90-95% (and/or a PaO2 of 60-80 mmHg); this is virtually equivalent to a patient having a
 PaO2/FiO2 of <100 mmHg at a PEEP level of ≥16 cmH2O. In such cases, the rest of the
 above-described, protocolized adjustments and interventions of the HFO-RMs protocol will
 be used without any additional change; rationale: TGI may be useful in patients, who
 require maximal support during CMV to maintain a clinically acceptable level of
 oxygenation (3).

 Rescue Oxygenation Patients of both groups will be eligible for rescue oxygenation if they
 fulfill the following criterion: Patient is on CMV with an FiO2 of 1.0 and a PEEP level of
 ≥20 cmH2O, and has a sustained and life-threatening hypoxemia (i.e., PaO2<60 mmHg for >30
 min), not associated with a "promptly reversible" factor (e.g. pneumothorax, malpositioning
 or obstruction of the tracheal tube, or ventilator malfunction). Rescue oxygenation
 techniques may include the use of HFO-RMs and/or HFO-TGI, prone position (14), inhaled nitric
 oxide (Nitric Oxide - ΝΟ), intravenous almitrine, and extracorporeal membrane oxygenation.
 The use of one or more rescue oxygenation techniques will last at least until the achievement
 of the reversal of the life-threatening hypoxemia for 1 hour.

 Patient follow-up Baseline patient data will be recorded within 2 hours pre-randomization.
 Daily recordings will include physiologic/laboratory data (days 1-28 post-randomization),
 intervention-associated complications (days 1-10; examples: RM-induced hypotension or
 desaturation), mechanical ventilation-associated barotrauma [study-independent radiologists
 will assess chest radiographs for pathologic gas collection(s), e.g. pneumothorax], data on
 organ/system failures and medication (days 1-60), episodes of failure to maintain unassisted
 breathing and various complications (until hospital-discharge or death; examples: infections,
 heparin-induced thrombocytopenia).

 During days 1-10, sets of physiologic measurements will be obtained as follows: 1) CMV group:
 3 measurements/day, starting at 8:30 a.m. 2) HFO-RMs group: just before, during, and 6 hours
 after HFO, and as in CMV group after day 5. Measurements will include arterial/central-venous
 blood-gas analysis, hemodynamics, and respiratory mechanics while on CMV (including
 respiratory compliance); also, on the morning of each one of days 1-10, we will determine and
 record the fluid balance of the preceding 24 hours. For between-group comparisons, we will
 use CMV-data obtained within 8:30-9 a.m. in both groups. Daily fluid balance will also be
 compared between the 2 groups.

 Lastly, in patients who have received HFO-TGI during days 1-5, a brief fiberoptic inspection
 of the trachea will be conducted on the morning of day 6 to detect any potential,
 TGI-associated tracheal mucosal damage. Bronchoscopic findings will be defined as follows:
 Grade I: Pink and glistening tracheal mucosa; Grade II: Reddened and/or swollen mucosa
 with/without presence of purulent secretions; Grade IIIA: Hemorrhagic mucosa and/or presence
 of thrombotic material; Grade IIIB: Limited localized necrosis, especially at the carina,
 and/or presence of necrotic mucosal slough; and Grade IIIC: Extensive localized necrosis,
 especially at the carina, and/or presence of necrotic mucosal slough. Grade IIIA-IIIC
 findings will be considered as suggestive of TGI-related mucosal damage. A bleeding diathesis
 (if present) should be considered as an independent risk factor for Grade IIIA findings.
 Findings suggestive of TGI-related tracheal mucosal damage in a patient will result in no
 further use of HFO-TGI for rescue oxygenation in that particular patient.

 Bronchoalveolar lavage (BAL) BAL of ≤100 mL will be performed on day 1 and 6
 post-randomization in patients of both groups. Patients will be eligible for BAL if their
 PaO2/FiO2 has been maintained at >100 mmHg for >12 hours and they are intubated with an
 orotracheal tube with an internal diameter of ≥8.5 mm, or a tracheostomy tube. An
 (additional) RM will be performed after the fiberoptic bronchoscopic procedure. BAL fluid
 samples will be used for microbiological cultures, cell count, and the determination of the
 concentration of phospholipids, surfactant-related proteins, and inflammatory markers. The
 purpose of the aforementioned investigational interventions is the elucidation of the effect
 of HFO on the function of the surfactant and the ARDS-related inflammation (15-18). During
 the bronchoscopic procedures, blood samples will also be obtained for the determination of
 the concentrations of the same inflammatory markers in the peripheral blood.

 BAL fluid studies The initial, 20-mL portion of the BAL fluid aspirate will be sent for
 microbiological cultures, and the rest will be stored in ice-cold tubes. Subsequently, the
 BAL fluid will be filtered through sterile gauze and centrifuged at 500 g for 15 min at 4 0C.
 The supernatant will be used for the determination of the concentrations of inflammatory
 markers, phospholipids, and surfactant-related proteins. The sediment will be used for total
 cell count, determination of cell type, and estimation of cell viability on a Neubauer plate.
 Both the supernatant and sediment will be stored at -700C.

 Surfactant aggregates, surfactant-related proteins, and inflammatory markers The cell-free
 supernatant of the 500 g centrifugation will be subjected to additional consecutive
 centrifugation at 30,000 g και 100,000 g for 90 min at 4 0C. This will be done to separate
 surfactant aggregates according to their size. The Large Surfactant Aggregates (LSAs) will be
 obtained from the 30,000 g centrifugation sediment. LSAs are considered as major determinants
 of the alveolar surface tension. The less active Small Surfactant Aggregates and the Very
 Small Surfactant Aggregates will be respectively obtained from the sediment and supernatant
 of the 100,000 g centrifugation (15).

 Surfactant studies will include total lipid concentration, separation of lipid classes with
 thin layer chromatography, determination of lipid phosphorus content (15), and
 surfactant-related proteins (17). In addition, the supernatant will be analyzed to determine
 the concentrations of tumor necrosis factor (TNF) alpha, interleukin (IL) 1-beta, IL-1
 receptor antagonist, IL-6, IL-8, transforming growth factor alpha (16,18), activin alpha, and
 folistatin, whereas the same inflammatory markers will be determined in the peripheral blood.

 POTENTIAL RISKS OF INVESTIGATIONAL INTERVENTIONS AND THEIR PREVENTION Potential risk:
 Barotrauma. Preventive measures: This potential risk is equally high during CMV or HFO
 (19,20). Prevention includes the rapid HFO-RMs-related improvement in oxygenation and lung
 compliance, and the consequent reduction in the ventilation pressures during the subsequent
 CMV. Regarding the theoretical risk of bronchoscopy-related barotrauma, the bronchoscopies
 will be performed by an experienced operator, and intra-procedural ventilation (comprising
 tidal volumes of 2-3 mL/kg predicted body weight at rates of 35/min and PEEP temporarily
 reduced to 0-5 cmH2O) will also be managed by an experienced physician. Potential risk:
 Hypotension-drop in cardiac output. Preventive measures: This potential risk is equally high
 during CMV or HFO (19,20). If RM-associated, RMs will be aborted for ≥10 hours (this holds
 also for cases of RM-induced desaturation - see above). TGI-related complications: Such
 complications are not expected, because there will be only short-term use of TGI (1-4).
 Nevertheless, TGI may cause tracheal mucosal damage, inspissation of secretions,
 pneumothorax, gas embolism, and hemodynamic compromise (1-4). In NCT00637507, 1 of the 61
 patients of the intervention group (1.6%) may have suffered a reversible tracheal mucosal
 injury (1). This patient had received TGI for a total of 118.3 hours over a period of 10 days
 (or 240 hours); he had a prolonged but full recovery from the severe ARDS and is currently
 leading a normal life.
Inclusion Criteria:

 1. early ARDS (establishment of the diagnosis within the preceding 72 hours) according to
 the criteria of the American-European Consensus Conference (5),

 2. Moderate-to-severe oxygenation disturbance [defined as ratio of partial pressure of
 arterial oxygen (PaO2) to inspired oxygen fraction (FiO2)<200 mmHg, while being
 ventilated with positive end-expiratory pressure (PEEP) set at ≥10 cmH2O for at least
 12 hours,

 3. age 18-75 years, body weight >40 Kg,

 Exclusion Criteria:

 1. severe air leak (more than one chest tubes per hemithorax with persistent air leak for
 more than 72 hours),

 2. systolic blood pressure lower than 90 mmHg and/or mean blood pressure lower than 65
 mmHg, despite maximum support with fluids and vasopressor drugs (i.e., norepinephrine
 infusion rate exceeding 0.5 μg/kg/min,

 3. significant heart disease (e.g. ejection fraction lower than 40%, history of pulmonary
 edema and active ischemic disease or myocardial infarction),

 4. severe chronic obstructive pulmonary disease (COPD) or asthma (e.g. previous admission
 for COPD/asthma, chronic treatment with corticosteroids for COPD/asthma, and chronic
 CO2 retention more than 50 mmHg),

 5. intracranial pathology with intracranial pressure >20 mmHg, not responsive to maximum
 conservative treatment (e.g. hemorrhage, head injury, tumor, infection or acute
 ischemic stroke),

 6. chronic interstitial lung disease with bilateral lung infiltrates,

 7. lung biopsy or incision during the current admission,

 8. previous lung transplantation or bone marrow transplantation, i) pregnancy,

 9. immunosuppression, and

 10. participation in another clinical study.