PRotective VENTilation in Patients Without ARDS
Condition: Ventilator-free Days
Study type: Interventional

Summary: 
      The purpose of this national multicentre randomized controlled trial is to compare a
      ventilation strategy using lower tidal volumes and higher respiratory rates with a
      ventilation strategy using higher tidal volumes and a lower respiratory rate in intubated and
      ventilated intensive care unit (ICU) patients without Acute Respiratory Distress Syndrome
      (ARDS) at start of ventilation.

      Participating centres in The Netherlands will include a total of 952 adult patients admitted
      to intensive care units without ARDS. Patients are randomized and ventilated with either a
      strategy with lower tidal volumes (4 to 6 ml/kg predicted body weight (PBW)) or a strategy
      with higher tidal volumes (8 to 10 ml/kg PBW). Patients will be assessed every day until day
      28 or discharge of the intensive care unit, whichever comes first, on day 28 and on day 90.
      Primary endpoint is the number of ventilator-free days at day 28. Secondary endpoints are
      ICU- and hospital length of stay (LOS) and - mortality, the incidence of development of ARDS,
      pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives, and
      neuromuscular blocking agents, incidences of ICU delirium and ICU acquired weakness,
      patient-ventilator asynchrony and the need for decreasing of instrumental dead space.
    

Detailed description: 
      Research question:

      Does mechanical ventilation with lower tidal volumes, as compared with mechanical ventilation
      with higher tidal volumes, increase the number of ventilator-free days at day 28 in patients
      without ARDS at start of ventilation?

      Study Design:

      An investigator-initiated, national, multicenter, parallel randomized controlled two-arm
      trial.

      Centers:

      Five centers in The Netherlands will participate in this trial;

        -  Academic Medical Center, University of Amsterdam

        -  Gelre Hospitals, Apeldoorn

        -  Leiden University Medical Center, Leiden

        -  Tergooi, Hilversum

        -  Vrije Universiteit University Medical Center, Amsterdam

        -  Westfries Gasthuis, Hoorn

      Ethics Approval: The Institutional Review Board of the Academic Medical Center approved of
      the study on 15 May 2014

      Monitoring:

        -  Monitoring of patients safety and reviewing of safety issues is performed by a
           designated independent Data Safety and Monitoring Board (DSMB).The DSMB watches over the
           ethics of conducting the study in accordance with the Declaration of Helsinki. This
           study compares two treatment strategies that are used in standard care, therefore no
           related serious adverse events (SAEs) are expected. All unexpected and related or
           possibly related adverse events will be reported to the DSMB

        -  An independent monitor will perform clinical trial monitoring. On-site monitoring will
           comprise controlling presence and completeness of the research dossier and the informed
           consent forms, source data checks will be performed. Every participating center will be
           visited at least once every year.

      Study Population:

      Adult ICU-patients without ARDS with an expected duration of ventilation longer than 24
      hours, within 1 hour after initiation of ventilation or admittance to the ICU if already
      intubated and ventilated on admission.

      Sample Size Calculation:

      The required sample size is calculated using data from the recently published meta-analysis
      and a secondary analysis of this meta-analysis using individual patient data from the studies
      performed in ICU patients [submitted for publication]. The sample size is computed on the
      basis of the hypothesis that ventilation with lower tidal volumes is associated with a
      reduction of one day of ventilation. A sample size of 397 patients in each group has 80%
      statistical power to detect a difference of one ventilator-free day and alive at day 28 after
      ICU admission, with means of 23 and 24 days respectively. Assuming that the common standard
      deviation is 5 using a two group t-test with a 0.05 two-sided significance level. The sample
      size is increased by 20% to correct for dropouts and lost to follow up (i.e., because
      patients could be transferred to other hospitals), meaning that each group will contain 476
      patients.

      Methods:

      Patients in participating intensive care units (ICU) are screened and randomized within 1
      hour of start of mechanical ventilation in the unit. Demographic data on screened patients
      regardless of meeting enrollment criteria will be recorded (registry: age, gender, type of
      surgery). Randomization will be performed using a dedicated, password protected,
      SSL-encrypted website. Randomization sequence is generated by a dedicated computer
      randomization software program using random block sizes and is stratified per center and per
      intubation location (i.e., in the ICU or before ICU admittance in the operation room or in
      the emergency room). No blocking is applied to other trial factors. Due to the nature of the
      intervention, blinding is not possible.

      Patients are randomly assigned in a 1:1 ratio to lower tidal volume ventilation (4 to 6 ml/kg
      PBW) (the 'lower tidal volume'-arm) or ventilation with higher tidal volumes (8 to 10 ml/kg
      PBW) (the 'higher tidal volume'-arm).

      The allowed ventilation modes are volume controlled ventilation and pressure support
      ventilation. The inspiration-to-expiration ratio with volume controlled ventilation is 1:2.
      With volume controlled ventilation the inspiration time and pause are set at 25% and 10%
      respectively. With pressure support ventilation the highest possible pressure rise is chosen,
      and cycling off is set at 25%. The inspired oxygen fraction is 0.21 or higher to maintain
      oxygen saturation 90 to 92% and/or PaO2 > 7.3 to 10.7 kPa (55 to 80 mmHg). The respiratory
      rate is adjusted to maintain a blood pH of 7.25 to 7.45. In case of metabolic acidosis or -
      alkalosis, a lower or higher than normal PaCO2 can be accepted, left to the discretion of the
      attending physician. The lowest level of positive end-expiratory pressure is 5 cmH2O.
      Recruitment maneuvers are allowed, when deemed necessary, left to the discretion of the
      attending physician. In both arms a tidal volume is titrated per PBW, which is calculated
      according to a previously used formula: 50 + 0.91 x (centimeters of height - 152.4) for males
      and 45.5 + 0.91 x (centimeters of height - 152.4) for females.

        -  Patients randomized to the 'lower tidal volume'-arm start with a tidal volume of 6 ml/kg
           PBW. The tidal volume size is decreased in steps of 1 ml/kg PBW per hour, to a minimum
           of 4 ml/kg PBW, unless the patient suffers from severe dyspnea (identified by increased
           respiratory rate > 35 breaths per minute accompanied by increasing levels of discomfort
           with or without need for more sedation) or unacceptable acidosis.The following measures
           can be taken to prevent respiratory acidosis: increasing respiratory rate and decreasing
           instrumental dead space by shortening ventilation tubing, to limit dead space
           ventilation. Patients randomized to the lower tidal volume arm may need very little
           support when the ventilator is switched to pressure support ventilation, but a minimum
           of 5 cmH2O should be used. In case the resulting tidal volume exceeds 6 ml/kg PBW this
           must be accepted

        -  Patients randomized to the 'higher tidal volume'-arm start with a tidal volume of 10
           ml/kg PBW. With volume-controlled ventilation the plateau pressure should not exceed 25
           cm H2O. Only if the plateau pressure exceeds 25 cm H2O the tidal volume is decreased in
           steps of 1 ml/kg PBW per hour, to a minimum of 8 ml/kg PBW (table 1). With pressure
           support, tidal volume titration is by variation of the pressure support level. Other
           modes of ventilation are not allowed.Patients randomized to the higher tidal volume arm
           generally need more support when the ventilator is switched to pressure support
           ventilation, but the maximal airway pressure should not exceed 25 cm H2O [2]. In case
           the resulting tidal volume remains below 10 ml/kg PBW this must be accepted.

        -  Daily assessment of the ability to breathe with pressure support ventilation is required
           as soon as FiO2 ≤ 0.4 or when the PEEP level and FiO2 level are lower than the day
           before. Other modes of ventilation are not allowed.In addition, the ventilator can be
           switched to pressure support ventilation at any moment the attending nurse or physician
           consider the patient is awake enough to breathe with pressure support ventilation.
           Assessment of the ability to breathe with pressure support is also required in case
           patient-ventilator asynchrony is noticed (ineffective breathing; double triggering, use
           of assessory respiratory muscles). A patient is assumed to be ready for extubation when
           the following criteria are met for at least 30 minutes, the final decision for
           extubation is made by the attending physician:

             -  Responsive and cooperative

             -  Adequate cough reflex

             -  PaO2/FiO2 of > 200 mmHg with FiO2 ≤ 40%

             -  Respiratory rate of 8 to 30/minute

             -  No signs of respiratory distress (i.e., marked accessory muscle use, abdominal
                paradox, diaphoresis, marked dyspnea)

             -  Pressure support level < 7 cm H2O (lower tidal volume arm) or < 12 cm H2O (higher
                tidal volume arm)

             -  Hemodynamically stable (systolic blood pressure 80 to 160 mmHg and heart rate 40 to
                130/min) and no uncontrolled arrhythmia

             -  Temperature > 36.0oC and < 38.5oC In the higher tidal volume arm physicians and
                nurses may decide to lower the pressure support level first (i.e., before
                extubation). For this, the pressure support level is lowered step-wise with steps
                of 2 to 5 cm H2O per hour to < 7 cm H2O. If this is not tolerated according to the
                conditions mentioned above, the pressure support level is set back to maintain a
                tidal volume as per randomization and the patient is assessed for extubation the
                following day. If a patient becomes able to breathe without assistance but
                subsequently requires additional ventilation within 28 days after randomization,
                the same tidal volume protocol is resumed. Non-invasive ventilation is allowed, but
                it should be tried to have comparable tidal volumes as with invasive ventilation,
                as per randomization.

      Sedation follows the local guidelines for sedation in each participating units. In general,
      these guidelines favor the use of analgo-sedation over hypno-sedation, use of bolus over
      continuous infusion of sedating agents, and the use of sedation scores. Nurses determine the
      level of sedation at least 3 times per day. The adequacy of sedation in each patient is
      evaluated using a Richmond Agitation Sedation Scale (RASS). A RASS score of -2 to 0 is seen
      as adequate sedation. As stated above, sedation adjustments should never be done to allow a
      lower or higher tidal volume. The goals of sedation are to reduce agitation, stress and fear;
      to reduce oxygen consumption (heart rate, blood pressure and minute volume are measured
      continuously); and to reduce physical resistance to- and fear of daily care and medical
      examination. Patient comfort is the primary goal.

      Statistical Analysis:

        -  The primary outcome, the number of ventilator-free days at day 28 after ICU admission,
           is analyzed using Cox's regression. Possible imbalance between groups will be modeled in
           the Cox model. P-values of 0.05 are used for statistical significance. When appropriate,
           statistical uncertainty will be expressed by the 95% confidence levels.

        -  Continuous normally distributed variables will be expressed by their mean and standard
           deviation or when not normally distributed as medians and their interquartile ranges.
           Categorical variables will be expressed as n (%). To test groups Student's t test will
           be used, if continuous data is not normally distributed the Mann-Whitney U test will be
           used. Categorical variables will be compared with the Chi-square test or Fisher's exact
           tests. Time dependent data will be analyzed using a proportional hazard model adjusted
           for possible imbalances of patients' baseline characteristics. Patient characteristics
           will be compared and described by appropriate statistics.

        -  The goal of the primary analysis is to quantify the effect of lower tidal volumes vs.
           higher tidal volumes on the number of ventilator free days and alive at day 28.
           Statistical analysis will be based on the intention-to-treat principle. We will also
           perform a per-protocol analysis, comparing patients who received lower tidal volumes and
           patients who received higher tidal volumes. Other secondary analyses include analysis of
           patients who had pneumonia versus patients without pneumonia, patients who fulfilled the
           definition for mild ARDS versus patients who did not fulfill this definition, and
           patients with sepsis versus patients without sepsis.
    

Intervention name(s): low tidal volume; high tidal volume
Intervention type(s): Procedure; Procedure
Intervention description(s): Patients are randomized and ventilated with a low tidal volume (4-6 ml/kg PBW); Patients are randomized and ventilated with a high tidal volume (8-10 ml/kg PBW)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: low tidal volume; high tidal volume; protective ventilation; ARDS