Respiratory Distress Syndrome Clinical Trial
Official title:
Phase II/Phase III Study of the Effect of Combined High-frequency Oscillation and Tracheal Gas Insufflation on the Survival to Hospital Discharge of Patients With Severe Acute Respiratory Distress Syndrome
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.
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
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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