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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.
Full 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;
Ethics Approval: The Institutional Review Board of the Academic Medical Center approved of the study on 15 May 2014
Monitoring:
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:
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:
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952 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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