Administrative information
Title {1} | 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 |
Trial registration {2a and 2b}. | NCT05740397 (retrospectively registered on ClinicalTrials.gov; 22/02/2023): https://clinicaltrials.gov/ct2/show/NCT05740397?term=NCT05740397&draw=2&rank=1 |
Protocol version {3} | Version 2 of 27-03-2021 |
Funding {4} | The project does not receive any source and any other type of financial, material or other supports |
Author details {5a} | AF. GM, AG. DL. LSB. GBL. FO. Division of Cardiac Surgery; Department of Surgery, Dentistry, Paediatrics and Gynaecology; University of Verona; Italy. |
Name and contact information for the trial sponsor {5b} | No external sponsor. |
Role of sponsor {5c} | No external sponsor. |
Introduction
Background and rationale {6a}
Objectives {7}
Primary objective
Secondary objectives
-
Intraoperative cerebral perfusion (through monitoring of the NIRS values)
-
Intraoperative pulmonary perfusion (through Pa/FiO2 ratio, paO2, paCO2 at blood gas analysis, and VO2R and DO2 at CDI® Blood Parameter Monitoring System 550)
-
Intraoperative and postoperative low cardiac output syndrome (according to the values of vasoactive inotropic score, VIS) [22]
-
Postoperative cardiac function (measuring left ventricular ejection fraction, LVEF)
-
Postoperative respiratory failure (through the values of Lung Injury Score, LIS, scale) [23]
-
Postoperative stroke and entity of transitory or permanent neurological damage (through score of modified Rankin Scale—mRS) [24]
-
Postoperative acute kidney injury (through AKI score)
-
Postoperative hepatic failure (measuring the hepatic function and coagulation indices)
-
Postoperative gastrointestinal ischaemia
-
Postoperative cardiovascular death, or death due to other causes
-
Stroke and entity of the transitory or permanent neurologic damage (mRS score)
-
Acute kidney injury (AKI score)
-
Cardiac function (LVEF)
-
Re-hospitalization
-
Death for cardiovascular or other causes
Trial design {8}
Methods: participants, interventions and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion criteria
-
Age > 18 years and < 80 years
-
Elective surgery
-
Index of surgical risk EuroSCORE II < 9%
-
The following procedures will be considered: Isolated or combined with aortic or mitral valve surgery coronary artery bypass graft surgery for acute or chronic coronary artery disease isolated aortic valve replacement for aortic stenosis and/or aortic regurgitation; isolated mitral valve repair or replacement for mitral stenosis and/or mitral regurgitation; isolated ascending aorta surgery with or without aortic valve replacement
-
Surgical approach through complete and/or mini sternotomy
-
Preserved or mildly reduced left ventricular ejection fraction (LVEF ≥ 40%) at preoperative echocardiography.
-
Patients with an estimated glomerular filtration rate (eGFR) ≥ 40 ml/min/mq calculated using the Modification of Diet in Renal Disease formula (MDRD)
-
Signed informed consent
Exclusion criteria
-
Age < 18 years and >80 years
-
Reoperation
-
Emergent, urgent and salvage procedures
-
EuroSCORE II > 9%
-
Right thoracotomy approaches
-
Any surgical procedure not listed above (i.e. tricuspid valve surgery, aortic root surgery, congenital heart diseases, surgery necessitating hypothermic circulation arrest, surgical ablation of atrial fibrillation, etc.)
-
More than mild left ventricular dysfunction at preoperative echocardiogram (LVEF < 40%)
-
Patients with critical preoperative state: any ventricular fibrillation or ventricular tachycardia, preoperative cardiac massage, preoperative ventilation before anaesthetic room, preoperative inotropes or mechanical circulatory support planned before cardiac intervention (i.e. during coronary angiography) and other conditions according to EuroSCORE II definition.
-
Patients with an estimated eGFR < 40 ml/min/mq calculated using the MDRD or patients on dialysis.
-
Patients with chronic obstructive pulmonary disease > 3 stage according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 classification.
-
Patients with severe preoperative hepatic failure (CHILD-PUGH ≥ B)
-
Patient with severe symptomatic carotid atheromasia
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Procedures
Preoperative
-
Clinical evaluation of the patient and eligibility for the study through collection of anamnestic data and physical examination.
-
Collection of informed consent for participating the study
-
Randomization
-
Measurement of preoperative MAP in every patient enrolled, regardless of the assignment group through randomization.
-
Blood samples to assess: haemoglobin (Hb), haematocrit (Ht), white blood cells (WBC), platelets (Plt), C reactive protein (CRP), lactate dehydrogenase (LDH), prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), fibrinogen and creatinine (mg/dl), lipase, pancreatic amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Bil Tot), conjugated bilirubin (direct Bil), unconjugated bilirubin (indirect Bil), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and albumin
-
Arterial blood gas test (ABG) to evaluate preoperative lactatemia
-
Calculation of eGFR (according to MDRD) to evaluate preoperative renal function
-
Evaluation of preoperative mRS in case of stroke in amnestic history.
-
A continuous monitoring of blood pressure will be performed invasively by cannulating the radial or femoral artery, as is customary in cardiac surgery. Data of MAP will be recorded at the beginning of CPB, every 20 min until minute 300 and at the end of CPB.
-
ABG after orotracheal intubation, at the beginning of CPB, every 20 min during CPB (eventually until minute 300), at the end of CPB, at the end of surgery. Data collected: lactates as organ perfusion index, Hb and Hct.
-
Real-time and continuous monitoring of respiratory gases during CPB suggestive of the perfusion trend, through CDI ® 550 Blood parameter monitoring system (Terumo Europe) [25], data collection related to oxygen delivery (DO2), oxygen consumption (VO2) and oxygen extraction (O2ER), at the beginning of CPB, every 20 min (until minute 300) and at the end of CPB.
-
Intraoperative monitoring of Near-Infrared Spectroscopy NIRS [26] defined as non-invasive measurement of cerebral microcirculatory blood flow. Data will be collected at anaesthesia induction, before skin incision, at the beginning of CPB, every 20 min (until minute 300), at the end of CPB and at the end of surgery.
-
Monitoring of CPB and aortic cross-clamp times
-
Calculation of “vasoactive inotropic score” (VIS) [22] which relates the entity of inotropic and or vasoactive support. VIS max is obtained through the following calculation: [Dopamine dose (mcgkg/min)+ Dobutamine dose (mcg/kg/min) + 100 × Epinephrine dose (mcg/kg/min) + 50 × Levosimendan dose (mcg/kg/min) + 10 × Milrinone dose (mcg/kg/min) + 10,000 × Vasopressin dose (units/kg/min) + 100 × Norepinephrine dose (mcg/kg/min)]. The VIS will be calculated according to the length of surgery.
-
Monitoring of nitroglycerine dose during surgery
Postoperative
-
Blood chemistry samples
-
Calculation of eGFR (according to MDRD)
-
ABG at arrival in ICU, at 3–6–12–24 h after surgery. Data collection on serum lactates, pH, paO2, paCO2, BE, HCO3−, calculation of the Pa/Fi ratio
-
Chest X-ray and evaluation of eventual pulmonary damage through Murray “Lung Injury Score” (LIS) [23]. The score considers 4 criteria for the development of ALI/ARDS: hypoxemia, respiratory system compliance, chest radiographic findings and the positive expiratory pressure level. Each criteria receives a score from 0 to 4 according to the gravity of the condition. The final score is obtained dividing the collective score by the number of components used. A score equal to 0 shows the absence of pulmonary damage, a score between 1 and 2.5 shows a mild to moderate pulmonary damage and a final score major than 2.5 shows the presence of ARDS.
-
Monitoring of estubation time (hours)
-
Calculation of VISmax
-
Monitoring of postoperative cardiac function at POD 4 through echocardiogram and evaluation of LVEF
-
Monitoring of postoperative stroke; a diagnosed stroke by a neurologist according to clinical, radiological (CT scan and/or MRI) and electrophysiological examination (EEG). Patients affected by stroke will undergo “modified Rankin Scale” (mRS) calculation which evaluates the degree of disability following a stroke and will be compared to the preoperative mRS. The score goes from a minimum score of 0 (no disability) to 6 (death).
-
Evaluation of acute kidney injury according to the definition of “Acute Kidney Injury” (AKIN) [27] through a stratification of renal damage in three stages: [1] Creatinine × 1.5–2.0 from baseline or Creatinine increased by at least 0.3 mg/dl (26.5μmol/L) [2]; Creatinine × 2.0–2.9 from baseline [3]; Creatinine > 3.0 from baseline or Creatinine increased at least 4 mg/dl (353.6 μmol/l) or the initiation of dialysis.
-
Monitoring of gastrointestinal ischaemia: a diagnosed ischaemia by a surgery consultant according to the value of serum lactate, WBC, clinical and radiological (CT scan and/or abdomen ultrasound) examination.
-
Monitoring of in-hospital death
-
Stroke and eventual transitory or permanent neurological damage (mRS score)
-
Acute kidney injury (eGFR and AKIN score)
-
Cardiac function (LVEF)
-
Re-hospitalization
-
Death for cardiovascular or other causes.
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome
Secondary outcomes
-
The area under the curve (AUC) of the serum lactate values measured during CPB
-
Number of cases with serum lactate peak > 3 mmol/l during CPB
-
Evaluation of intraoperative cerebral perfusion (through monitoring of NIRS)
-
Intraoperative pulmonary perfusion (through Pa/Fi ratio, paO2, paCO2 at ABG and VO2R and DO2 of CDI)
-
Evaluation of intraoperative and postoperative low cardiac output syndrome (through the calculation of VISmax)
-
Postoperative and 30-day LVEF (%)
-
Evaluation of pulmonary injury (through the LIS)
-
Postoperative and 30-day Acute Kidney Injury (according to AKIN score)
-
Postoperative gastrointestinal ischaemia
-
Hepatic function and coagulation indexes
-
Evaluation of neurological dysfunction (as dichotomous variable) and evaluation through mRS (0–6) in case permanent neurological injury
-
In-hospital mortality and at 30 days from surgery
-
Re-hospitalization
Participant timeline {13}
Sample size {14}
-
Cardiac Surgery Division of AOUI Verona: 327 cases (109 per group)
-
Cardiac Surgery Division of Ospedale Maggiore di Parma: 162 cases (54 per group)
-
Cardiac Surgery Division of Azienda Sanitaria Universitaria Friuli Centrale di Udine: 231 cases (77 per group)
-
Cardiac Surgery Division of Hospital Clinic de Barcelona, Spain: 279 cases (93 per cases)