Respiratory Failure Clinical Trial
Official title:
Mechanical Ventilation During Cardiac Surgery, a Randomized Controlled Trial
Background There is no unanimous opinion about a lung-protective strategy in cardiac
surgery. Small randomized clinical and animals trials suggest that ventilation during
cardio-pulmonary bypass (CPB) could be protective on the lungs. This evidence is based on
surrogate end-points and most of studies are limited to elective coronary surgery. According
to the available data, an optimal strategy of lung protection during CPB cannot be
recommended. The purpose of the CPBVENT study is to investigate the effectiveness of
different ventilation strategies during CPB on post-operative pulmonary complications.
Trial design The CPBVENT study will be a single-blind, multicenter, randomized controlled
trial. We are going to enroll 780 patients undergoing elective cardiac surgery with planned
use of CPB, aortic cross-clamping and two lung ventilation. Patients will be randomized into
three treatment groups: 1) no ventilation during CPB; 2) continuous positive airway pressure
(CPAP) with positive end-expiratory pressure (PEEP) of 5 cmH2O during CPB; 3) ventilation
with 5 acts/minute with tidal volume of 2-3 ml/Kg and a PEEP of 3-5 cmH2O during CPB. The
primary end-point will be the incidence of a PaO2/FiO2 ratio <200 until the time of
discharge from the ICU. The secondary end-points will be the incidence of post-operative
pulmonary complications and 30-days mortality. Patients will be followed-up to 12 months
after the date of randomization.
Summary The CPBVENT Trial will determine whether different ventilation strategies during CPB
will improve pulmonary outcome in patients undergoing cardiac surgery.
BACKGROUND Respiratory failure (RF) is a common complication in cardiac surgery, with a
global incidence of 20-25% . Its clinical manifestation ranges from a mild form of
respiratory failure up to an acute respiratory distress syndrome (ARDS) requiring prolonged
mechanical ventilation (MV) and intensive care unit (ICU) stay.
The pathophysiologic mechanism of RF is quite complex, but it is known that cardiopulmonary
bypass (CPB) plays a main role in determining lung injury. A number of factors contribute to
this injury: atelectasis, hyper-oxygenation causing the release of free radicals and
CPB-related systemic inflammatory response.
It's a common practice to suspend ventilation during CPB, since lung function is carried out
by an extracorporeal gas-exchanger. Moreover the absence of lung movements clearly
facilitates surgery. However, the interruption of MV during CPB is associated with the
development of micro-atelectasis, hydrostatic pulmonary edema, reduced lung compliance and
surfactant diffusion.
A recent observational study has identified the duration of CPB as an important risk factor
for the development of microbiologically-documented pneumonia.
During last years' several preventive lung protective strategies have been investigated and
proposed: ultrafiltration to remove neutrophils, controlled hemodilution (with hematocrit
higher than 23%), steroids and MV settings during CPB, such as the application of a Positive
End-Expiratory Pressure (PEEP) or a Continuous Positive Airway Pressure (CPAP) 5-15 of
cmH2O, low tidal-high frequency ventilation (100 acts-per-minute), application of 100%
oxygen inspired fraction (FiO2), and bilateral CPB, which involves lungs for
blood-oxygenation.
A recent meta-analysis based on sixteen clinical trials found an increase in oxygenation and
a reduction in shunt fraction immediately after the weaning from CPB if CPAP was applied
during CPB. Similar results were obtained with a lung recruitment maneuver at the end of
CPB. Furthermore, maintaining MV during the whole duration of extracorporeal circulation
would reduce the CPB-related inflammatory response and tissue damage. Unfortunately,
although adequately planned, studies are not powered enough to recommend maintaining MV
during CPB as an evidence-based strategy to prevent respiratory complications, because major
indicators of clinical outcome (i.e., duration of postoperative MV, length of ICU and
hospital stay, and long-term follow-up) have not been investigated. Therefore, according to
the available data in literature, an unquestionable standardized strategy of lung protection
during CPB cannot be recommended.
Objectives We designed a randomized controlled trial to investigate the effects of three
different ventilator strategies in the short, medium and long term. We are testing the
hypothesis that MV during CPB would reduce lung damage, defined as the incidence of RF
(PaO2/FiO2 < 200) and post-operative pulmonary complications (PPCs). See Appendix 1 for
complete definition of PPCs.
METHODS Trial design The CPBVENT study is a non-pharmacological, multi-center, single-blind,
randomized controlled trial.
The study has been registered on ClinicalTrials.gov with the registration number NCT02090205
and was endorsed by the Study Group on Cardiothoracic and Vascular Anesthesia of the SIAARTI
(the Italian Society of Anesthesia and Intensive Care Medicine).
Participants After Ethics Committee approval, we are going to enroll patients aged 18 or
over undergoing elective cardiac surgery with planned use of CPB, aortic cross-clamping,
median sternotomy and two lung ventilation. All patients will provide written informed
consent before their inclusion in the trial.
End-points The primary end-point will be the reduction of incidence of PaO2/FiO2 ratio <200
until the discharge from the Intensive Care Unit (ICU).
The secondary end-points will be the evaluation of the following:
- readmission to the ICU for RF,
- need for re-intubation,
- need for noninvasive ventilation,
- duration of mechanical ventilation,
- length of the ICU and hospital stay,
- cardiovascular complications,
- short-term and long-term mortality,
- post-operative infections,
- Post-Operative Residual Curarization (PORC): measured with a Train Of Four (TOF) and
defined as need for pharmacological reversal.
Interventions (Randomization and treatment protocol) The randomization list was created by
the coordinating center with a dedicated software and was stratified per center, in a 1:1:1
ratio, in blocks of 30. Once the patient releases informed consent, the investigator will
log in on a dedicated on line portal and he will obtain the allocation arm. From that moment
it will be impossible to remove the patient's record card from the online platform and, in
any case, the patient will be analyzed according to the intention-to-treat principle. Any
deviation from the ventilation protocol, together with reason for deviation, will be
recorded on the CRF. All the patients will be kept blind to the allocation.
Patients will be randomly assigned to receive one of the following ventilator strategies:
- First arm. No mechanical ventilation during CPB: patient will be disconnected from the
respiratory circuit.
- Second arm. Patients will receive CPAP with PEEP of 5 mmH2O and FiO2 < 80%. To perform
CPAP the ventilator will be set in manual/spontaneous mode, with a flow of 1-2 L/min
and the adjustable pressure valve (APL) set at 5 cmH2O. The actual pressure will be
checked with a pressure gauge integrated in the ventilator and a pressure gauge
connected to the proximal end of the endotracheal tube.
- Third arm. Patient will be ventilated with a respiratory rate of 5 per minute, with
tidal volume (TV) of 2-3 mL/Kg of Ideal Body Weight (IBW) and PEEP of 3-5 cm H2O.
Before and after CPB patients will receive a lung-protective ventilator strategy, with an
Intermittent Positive Pressure Ventilation (IPPV) mode along with the following parameters:
- Tidal Volume (TV) = 6-8 ml/kg of IBW:
- PEEP = 5 cmH2O
- FiO2 <80%
- I:E = 1:2 (inspiration:expiration ratio). During CPB our goal will be to maintain a
PaO2 between 200 and 250 mmHg, in order to avoid hyperoxia-induced lung injury;
moreover the hematocrit will be maintained above 24%. During weaning from CPB we will
perform a single alveolar recruitment maneuver, with an airway pressure of 40 cmH2O
maintained at least for 7 seconds.
Post-operative ventilation The anesthesiologist will report in the Case Report Form (CRF)
the mechanical ventilation setting used during the transfer of the patient from the
operating theater to ICU. In ICU we will apply an IPPV with the same parameters used in the
operating room. Blood oxygen saturation will be constantly monitored with a pulseoxymeter.
We will report the extubation-time, the duration of mechanical ventilation and the need of
re-intubation. Blood gas analyses will be performed by the clinician according with clinical
needs.
Data collection Investigators will collect all the data on the dedicated CRF and will insert
all the information required in the online platform. The coordinator center will directly
receive all the information in a very simple data flow, with safe mechanisms for the
protection of personal clinical information. The website uses an https format and all
patients' data will be collected anonymously. We have also implemented regular backups, in
order to minimize the risk of data corruption.
After discharge from the hospital, patients will be phone-called for the follow-up. We will
record any re-admission in hospital or exitus. Follow-up will be performed 30 days, 60 days
and one year after randomization.
Statistical considerations Sample size Sample-size calculation was based on a two-sided
alpha error of 0.05 and a 80% power. On the basis of respiratory insufficiency incidence
after cardiac surgery we anticipate a 25% of patients with a PaO2/FiO2 < 200 ratio. We
expect the incidence of this parameter to be reduced of the 35%. We calculate that we will
need a sample size of 263 patients per group. Including a drop-out fraction of 10%, we
calculate that we will be needing 870patients to complete the trial.
Data analysis We will analyze patients in the treatment group to which they are allocated.
Data will be analyzed with a professional statistical software. Data will be analyzed
according to the intention-to-treat principle and following a pre-established analysis plan.
Dichotomous variables will be compared with the two-tailed Χ2 test, using the Yates
correction when appropriate. Continuous variables will be compared by analysis of variance
or the non-parametric Kruskal-Wallis test, when appropriate. Relative risks with 95%
confidence intervals and differences between medians with 95% confidence intervals (using
the Hodges-Lehmann estimation) will be calculated when appropriate. Two-sided significance
tests will be used throughout.
Subgroup analyses We will infer a subgroup effect if the interaction term of treatment and
subgroup is statistically significant at P <0.05.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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