Conservative vs Conventional Oxygen Administration in Critically Ill Patients: Effects on ICU Mortality. A Multicentre Randomized Open Label Clinical Trial

Objectives: The primary objective of this study is to verify the hypothesis that strict maintenance of normoxia improves survival in a wide population of mechanically ventilated critically ill patients compared to the application of conventional more liberal strategies of oxygen administration. Survival will be measured at Intensive Care Unit discharge. Secondary objectives are to verify the hypothesis that, in a wide population of mechanically ventilated critically ill patients, the strict maintenance of normoxia compared to the application of conventional more liberal strategies of oxygen administration reduces the 90-day mortality, onset of new organ failures (respiratory, cardiovascular, renal and hepatic after 48 hours from Intensive Care Unit admission) during Intensive Care Unit stay, occurrence of nosocomial infections during Intensive Care Unit stay (only microbiologically documented bloodstream, respiratory and surgical site infections will be considered), the length of mechanical ventilation, vasopressor use and Intensive Care Unit stay, the occurrence of Intensive Care Unit acquired weakness and cognitive dysfunction.

Intervention: On the Intensive Care Unit admission, or later when they fulfil eligibility criteria, participants will be randomly assigned to a group of liberal conventional oxygen administration (CONVENTIONAL) or a group of conservative experimental oxygen administration (CONSERVATIVE). Within the conventional group, participants will receive a FiO2 aiming to maintain a SpO2 equal or major than 98 percentage, accepting an upper limit of PaO2 of 150 mmHg and a lower limit of 60 mmHg. Patients in the conservative group will receive the lowest FiO2 to maintain SpO2 between 94 and 98 percentage, or when available a PaO2 between 60 mmHg and 100 mmHg. The changes in oxygen therapy will be according to a nurse order-set. The indications to non-invasive ventilation or tracheal intubation and invasive mechanical ventilation (and to the most appropriate mode of ventilatory support) will be guided by principles of the Good Clinical Practice and by the clinical judgement of the attending physician. No other pharmacological therapy or treatment will be influenced by the study protocol. There are no restrictions to concomitant treatments provided to patients in this study.

Sample size and recruitment: Assuming a two-sided alpha level inferior than 0.05 and a power of 80 percentage, we calculated that 460 patients are needed per arm to detect a relative risk reduction of 40 percentage (absolute risk reduction of 6 percentage) compared to a mortality of 15 percentage observed in conventional group patients in previous studies. The global sample size is established to 1,000 patients. This includes an additional 80 participants to allow for drop-outs and an expected temporal trend of reducing mortality at ICU discharge. Every month, recruitment status will be evaluated, and a newsletter will be disseminated, including any issue arisen. The study will end after 12 months of enrollment plus 90 days for follow up.

Allocation and blinding: A block randomisation will be used with variable block sizes, stratified by centre using a web-based, randomisation interface.

Data collection and management: The study data will be collected along the entire Intensive Care Unit stay in a dedicated Case Report Form, that will be provided by the steering committee with proper options to minimize data entry errors: the data sheet will incorporate unmodifiable fixed intervals of values (for continuous variables) and pre-defined coding system (for binary or categorical variables). Data entry will be performed and double-checked from a dedicated researcher in each centre; in order to limit collection errors, 10 percent of all records will be randomly re-checked from the Principal Investigator in each participating centre. Data will be collected in an electronic Case report Form and transmitted by a dedicated platform to the Research and Innovation Office of the University Hospital of Modena protected by password to prevent unintentional modifications or deletion. Database management and quality control for this study will be under the responsibility of the Clinical Trial Quality Team of the University Hospital of Modena. In addition, each satellite centre will monthly communicate and report via e-mail with the coordinating centre about the number of recruited patients, eventual missing data or missing visit or any kind of problem correlated to data collection. Data related to the study will be stored for eventual further analysis or study purpose for 5 years after the end of the study. All the data about the included patients will be extrapolated from the clinical documentation and recorded in a Case Report Form from an adequately formed researcher. Demographic information (gender, age), co-morbidities, reason of Intensive Care Unit admission, type of admission will be registered at the inclusion; severity of critical illness (quantified by the Simplified Acute Physiology Score II) will be calculated by the data from the first 24 hours of Intensive Care Unit stay. During the entire stay, Sequential Organ Failure Assessment score will be calculated and registered daily. Every partial score will be registered separately (Nervous System, Respiratory, Cardiovascular, Liver, Renal and Coagulative). Blood Gas Analysis results will also be reported: FiO2, PaO2, PaCO2, hydrogen ion concentration, lactates, bicarbonates, Base Excess. Other daily parameters: duration of ventilatory support in hours, need and dose of vasoactive drugs (doses reported in µg/Kg/min), need of renal replacement therapy subsequent to the first 24 hours of Intensive Care Unit stay. The occurrence of Intensive Care Unit-acquired respiratory, blood and surgical site infections and the implicated microorganisms will be registered. Data from routine laboratory test will be reported: haemoglobin, platelets count, white blood cells count, coagulative parameters, parameters for liver and renal function; Central venous oxygen saturation and arterial lactates will be reported when available. The patient will be followed-up until 90 days and for patients who have been discharged from the hospital during this follow-up, the information will be collected with a phone interview. The vital status may be ascertained through public registries, in case of failure of all other ways of contact.