Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02153294 |
| Other study ID # |
PReVENT-NL |
| Secondary ID |
80-83700-98-4200 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
May 23, 2014 |
| Last updated |
March 23, 2018 |
| Start date |
August 2014 |
| Est. completion date |
November 18, 2017 |
Study information
| Verified date |
March 2018 |
| Source |
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
