Study of a Novel Technique of Mechanical Ventilation in Patients With Severe Acute Respiratory Failure
Condition: Respiratory Distress Syndrome
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The investigators have recently demonstrated the beneficial effects of combined
      high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) on the respiratory
      physiology [1,2] of patients with severe acute respiratory distress syndrome (ARDS)
      (NCT00416260). Preliminary short-term survival results were also encouraging. Consequently,
      in the present clinical trial, the investigators intend to increase the size of the studied
      population, in order to evaluate the effect of HFO-TGI on survival with adequate statistical
      power. Furthermore, the investigators intend to elucidate the mechanism of the
      HFO-TGI-related physiological benefit.
    

Detailed description: 
      BACKGROUND AND OBJECTIVES

      The prognosis of ARDS still remains grave [3-7]. The primary objective of the present study,
      is to definitively determine the effect of HFO-TGI on the survival of patients with severe
      ARDS. Consequently, we will increase the size of the studied population (see also
      NCT00416260), in order to achieve sufficient statistical power. The secondary objective is to
      test the hypothesis that lung recruitment is the major underlying mechanism for the
      HFO-TGI-associated improvement in oxygenation [1,2] and respiratory compliance [2].

      METHODS

      Patients

      The protocol has been approved by the Scientific Committees of Evaggelismos Hospital and of
      Larissa University Hospital. Informed consent will be requested from the next-of-kin of
      participation-eligible patients. Patients will be informed of the trial and their right to
      withdraw as soon as clinically feasible. Eligibility criteria are presented in the
      appropriate section of this report. In brief, the major inclusion criteria will comprise 1)
      early (diagnosis established within the preceding 72 h) ARDS according to the
      American-European Consensus Conference Definition [6]; 2) severe oxygenation disturbances
      {defined as PaO2/FiO2) < 150 mm Hg}, while ventilated with a positive end-expiratory pressure
      (PEEP) of ≥ 8 cm H2O (criterion for severe ARDS); and 3) age 18-75 years and body weight > 40
      kg. Patient monitoring will include electrocardiographic lead II, hemodynamics {continuous
      intraarterial and central-venous pressure, and cardiac output/index by PICCO-plus (Pulsion
      Medical Systems, Munich, Germany)}, and peripheral oxygen saturation (SpO2). Deep sedation
      (propofol/midazolam) [8,9], analgesia (fentanyl/remifentanil) [9], and intermittent
      neuromuscular blockade (cisatracurium) [8,10] will be used.

      CMV Strategy

      In the 37-bed intensive care unit (ICU) of Evaggelismos hospital and the 10-bed ICU of
      Larissa hospital, a pressure-and volume-limited ventilatory strategy is routinely employed.
      Consequently, before randomization, patients will already be ventilated (Siemens 300C
      ventilator; or Galileo Gold, Hamilton Medical) with one of the ARDSnet-protocol allowable
      combinations of FiO2 and PEEP [11]. Administered tidal volumes will be 5.5-7.5 mL•kg-1
      predicted body weight, ventilatory rate (e.g., 20-35•min-1) will be adjusted so that pHa is
      kept in-between 7.20-7.45; the inspiratory to expiratory time ratio will be 1:1 to 1:3; and
      the target plateau inspiratory pressure will be ≤ 35 cm H2O. Oxygenation goals will be PaO2 =
      60-80 mm Hg or SpO2 = 90-95%.

      Randomization

      Patients will be assigned to the HFO-TGI-group (i.e., the intervention-group) or the
      Conventional Mechanical Ventilation (CMV)-group (i.e., the control-group) according to a
      computer-generated, random number-sequence (http://www.randomizer.org). Furthermore,
      crossover from the CMV)-group to the HFO-TGI-group will be performed whenever requested by
      the attending physicians. Randomization will be undertaken by the department's statistician
      and will be supervised by the Independent Main End Point and Safety Monitoring Committee,
      which will be the same as for NCT00416260, with an additional member at Larissa hospital.
      Group allocation will be concealed until study entry.

      HFO-TGI strategy

      Just prior to HFO-TGI initiation, a TGI catheter (internal / external diameter = 1.0 / 2.0
      mm, respectively) will be introduced into the endotracheal tube. TGI catheter tip will be
      placed 0.5-1 cm beyond the endotracheal tube tip. For TGI administration, the proximal end of
      the TGI catheter will be connected to a variable-orifice O2 flowmeter. The Sensormedics 3100B
      high-frequency ventilator will be connected to the endotracheal tube. Initial HFO settings
      will be as follows: 1) FiO2 = 100%, later-on titrated toward the FiO2 of preceding CMV; 2)
      bias flow = 30-40 L•min-1; 3) oscillation frequency = 4.0-5.0 Hz; 4) oscillatory pressure
      amplitude = arithmetical PaCO2 value during preceding CMV + 20-30 cm H2O, maximal acceptable
      value = 95-100 cm H2O [1]; 5) inspiratory to expiratory time ratio = 1:2; and 6) mPaw
      adjusted to 9-10 cm H2O above preceding CMV mPaw (corresponding to an HFO-mean tracheal
      pressure of 2-3 cm H2O above the mean tracheal pressure of the preceding CMV). Three-to-five
      mins after HFO initiation, a recruitment maneuver will be performed by pressurizing the HFO
      circuit at 40-45 cm H2O for 30-40 secs with oscillator piston off. HFO will then be resumed,
      and a 3-5 cm H2O endotracheal tube cuff leak will be placed. Immediately thereafter,
      continuous forward thrust TGI {flow = 50% of the minute ventilation of the preceding CMV [1]}
      will be superimposed on the HFO. The mPaw control knob will then be adjusted to return mPaw
      to its originally set value. Fifteen min thereafter, arterial blood gas analysis will be
      performed and oscillatory pressure amplitude and oscillation frequency will be adjusted, in
      order to achieve a PaCO2 of < 10-15 mm Hg above the PaCO2 of the preceding CMV and to keep
      pHa > 7.20. At 90 min after HFO-TGI initiation, physiologic measurements (i.e., blood gas
      analysis and hemodynamics) will be conducted, and then, mPaw will be gradually reduced
      (estimated reduction rate: 0-2 cm H2O•h-1) toward 6 cm H2O below its initially set value
      (corresponding to an HFO-mean tracheal pressure of 2-3 cm H2O below the mean tracheal
      pressure of the preceding CMV). Subsequently, TGI will be discontinued and standard HFO will
      be continued for 30 min.

      Return to CMV will be considered at the following HFO settings: mPaw = 3-4 cm H2O above
      preceding CMV mPaw (corresponding to an HFO-mean tracheal pressure of 2-3 cm H2O below the
      mean tracheal pressure of the preceding CMV); and TGI = 0 L•min-1. Return to HFO-TGI will be
      considered necessary if after 12 h of CMV, PaO2/FiO2 is < 150 mm Hg at a PEEP of ≥ 8 cm H2O.
      In the HFO-TGI-group, patients will receive repeated daily sessions of HFO-TGI until they no
      longer satisfy the severe ARDS criterion during CMV for at least 48 h. Predicted minimum
      duration of HFO-TGI sessions is 6 h. During HFO-TGI sessions, physiologic measurements will
      be performed every 1.5-4 h, and their average values will be used in the subsequent
      statistical analysis. For HFO-TGI-group members, total HFO-TGI duration will have to be > 12
      h.

      Recruitment Maneuvers

      Recruitment maneuvers (with continuous positive airway pressure of 40-45 cm H2O and a
      duration of 40 secs) will be performed as follows:

      In the HFO-TGI group, recruitment maneuvers will be performed at the onset and at 3 and 5 h
      following the onset of each HFO-TGI session, and just after to return to CMV. In the
      CMV-group, ≥ 4 recruitment maneuvers (one every 4-6 h; starting at 07:00) will be performed
      daily. In both groups, recruitment maneuvers will be continued for the first 4 days
      post-randomization [12].

      Weaning from CMV

      Weaning from CMV will be by pressure-supported ventilation when a PaO2 of > 60 mm Hg can be
      maintained at an FiO2 of ≤ 50% and a PEEP of ≤ 8 cm H2O.

      Data Collection

      Data on demographic, physiologic, and radiographic characteristics, coexisting conditions,
      and medication will be recorded within 4 h prior to randomization. For the first 10 days
      post-randomization, at least 3 sets physiologic measurements (blood-gas analysis,
      hemodynamics, and respiratory mechanics during CMV) will be obtained daily. Laboratory,
      radiographic/imaging, and physiologic data will be collected daily until ICU discharge or
      death. Patients will be monitored daily for signs of failure of nonpulmonary organs and
      systems. Patient clinical course will be documented until hospital discharge or death.

      Follow-up of Lung Recruitment with CT of the Thorax

      During the intervention period of the present study, we intend to assess and monitor the
      evolution of lung recruitment, as recently suggested and described in detail by Gattinoni and
      colleagues [13]. The recruitment-assessment protocol will be as follows: 1) HFO-TGI-group: CT
      of the thorax at baseline, and at days 5 and 8 post-randomization; 2) CMV-group: CT of the
      thorax at baseline, and at day 8 post-randomization. Patients will be considered as eligible
      for CT-evaluation if PaO2/FiO2 is in-between 100-150 mmHg, and if there is no additional
      concern with respect to patient transportation safety to the CT suite, as confirmed by the
      attending physicians on a case-by-case basis. The rationale for this investigational
      intervention comprises the elucidation of the mechanism of the HFO-TGI-induced physiological
      benefit.

      Outcome measures are mentioned in the appropriate section.

      In concordance with a suggestion of a recent Editorial (Intensive Care Med (2014)
      40:743-745), the Original and (its revision to) the Final Form of the Study Protocol (also
      corresponding to NCT00416260 which was registered as the first study period) detailing the
      Pre-specified Study Planning (which explains the reason for any prior changes in the current
      registration data) can be found by scrolling down to the end of the following webpage:
      http://www.evaggelismos-hosp.gr/index.php/istoriko-eepne
    

Intervention name(s): High-frequency Oscillation and Tracheal Gas Insufflation
Intervention type(s): Other
Intervention description(s): Patients will receive daily sessions of High-frequency Oscillation and Tracheal Gas Insufflation (HFO-TGI), which will last at least 6 hours. These sessions will comprise a recruitment period of at least 90 min, a stabilization period of at least 4 hours, and a weaning period of at least 60 min. The HFO-TGI strategy will be aimed at initially maximizing PaO2/FiO2 without causing hemodynamic compromise (e.g., >10% reduction in cardiac output/index), and subsequently maintaining PaO2/FiO2 >150 mm Hg, while gradually reducing mPaw to 4-6 cm H2O below its initial setting. The weaning from TGI and HFO will be according to the reversal of the oxygenation criterion that mandated their use (see also Detailed Description).
Other intervention name(s): HFO-TGI
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High-Frequency Ventilation; Tracheal Gas Insufflation; Respiration, Artificial; Respiratory Distress Syndrome; Adult