Mean Arterial Pressure (MAP) Trial: Study Protocol for a Multicenter, Randomized, Controlled Trial to Compare Three Different Strategies of Mean Arterial Pressure Management During Cardiopulmonary By-pass

Background:Most of cardiac surgery operations require a bloodless operating field and a steady heart (i.e. cardioplegic arrest). To ensure the perfusion of peripheral organs during the cardioplegic arrest time, the Cardipulmonary bypass (CPB) is installed. The CPB is a biomedical device, also named Heart-Lung machine, that, through a circuit, filtrates and oxygenates venous blood coming from the patient, giving it back as arterial blood through a mechanical pump. The blood flow produced by the CPB is continuous, then the pressure produced is a Mean Arterial Pressure (MAP). The MAP can be modulated by vasoactive and/or anaesthetic drugs during CPB, in order to maintain an appropriate perfusion pressures in all end-organs, avoiding tissue hypoperfusion and hypoxia. The latter, indeed, may occur in the post-operative period as organ damage: cerebral ischemia and consequently transitory or permanent neurological injury, renal ischemia and consequently acute kidney injury, or gastrointestinal ischemia. Consequently, the management of MAP acquires a crucial role. A value of 50-60 mmHg has been historically accepted as the "gold standard" MAP, according to the early experiments and pioneering cardiac surgery investigations. However, in the last decades, the CPB has remarkably changed thanks to the evolution of technology and availability of new biomaterials. Therefore, as already highlighted by the latest European Guidelines, the current management of CPB can no longer refer to those pioneering studies. To date, only few single-center studies focused their attention on the correlation between MAP values during CPB and cardiac surgery outcomes. One study compared the "high-target" MAP (70-80 mmHg) to "standard" MAP (50-60 mmHg) in terms of new post-operative cerebral injuries. They reported a higher incidence of stroke (7.0% vs 1.1%; P=0.09) and mortality (4.1% vs 0%; P=0.06) in the "high-target" MAP population compared to the "low-target" group. Conversely, another author, reported a reduction (from 12.9% to 4.8%) of major cardiac and neurologic events in patients treated with higher MAP compared to patients treated with the "standard" MAP during coronary artery bypass graft surgery (CABG). However, they are both single-center studies, with small sample sizes; moreover, the second one involves only CABG patients. Finally, a third author compared the "high-MAP" (80 mmHg) with "patient-tailored" MAP (comparable to pre-operative MAP in the single patient). The study showed no differences in terms of major cardiac and neurologic events (11.7% and 12.6% respectively), but also the study included only patients undergoing CABG surgery. However, all the above-mentioned studies showed conflicting evidences, without achieving a real consensus on what should be the most adequate MAP target during CPB.

The purpose of our randomized study is to define the best strategy to obtain an "ideal MAP" during CPB, comparing the historically accepted "standard MAP" (50-60 mmHg) with the "high MAP" (70-80 mmHg) and with the "patient-tailored MAP". To investigate the risk of hypoperfusion and to evaluate whether the MAP during CPB is adequate to avoid tissue hypoxia, the serum lactate value will be collected at different time-points, as index of tissue anaerobiosis/hypoperfusion. To date, several studies have analysed the trend of lactates intraoperatively and postoperatively, and hyperlactatemia demonstrated to be a predictive factor of post-operative mortality and morbidity. Particularly, some authors describe that a peak of lactates > 4 mmol/l during CPB relates to post-operative mortality. Another study considered a cut-off of 3 mmol/l, and also in this case, hyperlactatemia during CPB relates to post-operative major complications. However, both studies do not give information about the precise value of lactates reached, neither about the entire trend of lactates released during CBP. Therefore, differently from previous studies, the primary endpoint of this trial will be the peak value (absolute value) of serum lactates (Lmax) measured during CPB.

Methods: Participants, interventions and outcomes Study setting:Coordinator centre: Division of Cardiac Surgery, Azienda Ospedaliera Universitaria Integrata Verona, Italy.

Participating Centers:Center 1: Division of Cardiac Surgery at Ospedale Maggiore, Parma, Italy; Center 2: Division of Cardiac Surgery at Azienda Sanitaria Universitaria Friuli Centrale, Udine, Itay.Center 3: Division of Cardiac Surgery at Hospital Clinic de Barcelona, Barcelona, Spain Intervention description:The treatment groups will be:Group 1: Standard MAP: MAP values between 50-60 mmHg as control group. Group 2: High MAP: MAP values between 70-80 mmHg. Group 3: Patient-tailored MAP: MAP comparable to the patient's pre-operative MAP.

Procedures,Preoperative: Day before surgery: