Personalized Hemodynamic Management in High-risk Major Abdominal Surgery (PELICAN)

Personalized Hemodynamic Management Targeting Preoperative Baseline Cardiac Index in High-risk Patients Having Major Abdominal Surgery: the International Multicenter Randomized PELICAN Trial

Postoperative mortality within 30 days after surgery is around 2% in patients having major noncardiac surgery in Europe and the USA. In fact, if the first 30 days after surgery were considered a disease, it would be the third leading cause of death globally. Postoperative deaths are a consequence of postoperative organ injury and complications - including acute myocardial injury, acute kidney injury, and severe infectious complications. To avoid postoperative deaths, it is thus crucial to reduce postoperative organ injury and complications. To reduce postoperative organ injury and complications, modifiable risk factors need to be addressed. These modifiable risk factors for postoperative organ injury include low blood flow states and intraoperative hypotension. Optimizing blood flow (i.e., cardiac index) during surgery may thus be effective in reducing postoperative organ injury and complications. However, the optimal hemodynamic treatment strategy for high-risk surgical patients remains unclear. Cardiac index varies substantially between individuals. However, current intraoperative hemodynamic treatment strategies mainly aim to maximize cardiac index instead of using personalized cardiac index targets for each individual patient. A single-center pilot trial suggests that using individualized cardiac index targets during surgery may reduce postoperative organ injury and complications compared to routine hemodynamic management. However, large robust trials investigating the effect of personalized hemodynamic management targeting preoperative baseline cardiac index on postoperative complications are missing. The investigators, therefore, propose a multicenter randomized trial to test the hypothesis that personalized hemodynamic management targeting preoperative baseline cardiac index reduces the incidence of a composite outcome of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, severe infectious complications, and death within 7 days after surgery compared to routine hemodynamic management in high-risk patients having major abdominal surgery.

In patients in the routine management group, the treating anesthesiologists will be blinded to data of preoperative baseline cardiac output measurements to avoid performance bias. Participants and outcome assessors are blinded to group allocation.

In patients assigned to routine hemodynamic management, hemodynamic management will performed as per anesthesiologist preference. Cardiac index monitoring will be will measured using the Baxter Starling Fluid Management System (Baxter, Deerfield, IL, USA). The attending anesthesiologist will be blinded to cardiac index measurements. Cardiac index monitoring can be unblinded upon request. Mean arterial blood pressure will be maintained above 65 mmHg.

In patients assigned to personalized hemodynamic management, intraoperative cardiac index will be maintained at least at the preoperative baseline cardiac index measured the day before surgery using a predefined treatment algorithm. Preoperative baseline cardiac index will be determined at least one day before surgery with the patient being awake and resting in supine position using the Starling Fluid Management System (Baxter, Deerfield, IL, USA). We will define the individual preoperative baseline cardiac index as the average value over a 5 min period at rest (minimum cardiac index threshold: 2.2 L min-1 m-2). Mean arterial blood pressure will be maintained above 65 mmHg. The study intervention will start at the beginning of surgery and will end at the end of surgery.

Personalized hemodynamic management: Intraoperative cardiac index will be maintained at least at the preoperative baseline cardiac index. Preoperative baseline cardiac index will be determined one day before surgery with the patient being awake and resting in the supine position using the Starling Fluid Management System (Baxter, Deerfield, IL, USA). We will define the individual preoperative baseline cardiac index as the average value over a 5 min period at rest (minimum cardiac index threshold: 2.2 L min-1 m-2). Intraoperative cardiac index will be measured using the Baxter Starling Fluid Management System.

Collapsed composite ("any event versus none") of acute kidney injury, acute myocardial injury (including myocardial infarction), non-fatal cardiac arrest, severe infectious complications, and death within 7 days after surgery.

Collapsed incidence of acute kidney injury, acute myocardial injury (including myocardial infarction), non-fatal cardiac arrest, severe infectious complications, and death within 3 days after surgery.

Incidence of a composite outcome of fever, respiratory infection, neurological infection, urinary system infection, colitis or infection with Clostridium difficile, endometritis, surgical site infection, deep incisional surgical site infection, organ or space surgical site infection, unknown infection with pathogenic organisms in tissue or fluid, and sepsis within 3 days after surgery.

Incidence of a composite outcome of fever, respiratory infection, neurological infection, urinary system infection, colitis or infection with Clostridium difficile, endometritis, surgical site infection, deep incisional surgical site infection, organ or space surgical site infection, unknown infection with pathogenic organisms in tissue or fluid, and sepsis within 7 days after surgery.

Collapsed incidence of need for renal replacement therapy, myocardial infarction, non-fatal cardiac arrest, and death within 30 days after surgery

Collapsed incidence of need for renal replacement therapy, myocardial infarction, non-fatal cardiac arrest, and death within 90 days after surgery

Incidence of unknown infection with pathogenic organisms in tissue or fluid within 7 days after surgery

Time-to-event endpoint with the event "transfer from intensive care unit to normal ward" within 90 days after surgery

Inclusion Criteria: Consenting patients ≥45 years scheduled for elective major abdominal surgery under general anesthesia that is expected to last ≥90 minutes AND presence of ≥1 of the following high-risk criteria: exercise tolerance <4 metabolic equivalents as defined by the guidelines of the American College of Cardiology/American Heart Association renal impairment (serum creatinine ≥1.3 mg dL-1 or estimated glomerular filtration rate <90 mL min-1 (1.73 m2)-1 within the last 6 months coronary artery disease chronic heart failure (New York Heart Association Functional Classification ≥II) valvular heart disease (moderate or severe) history of stroke peripheral arterial occlusive disease (any stage) chronic obstructive pulmonary disease (any stage) or pulmonary fibrosis (any stage) diabetes mellitus requiring oral hypoglycemic agent or insulin immunodeficiency due to a disease (e.g., HIV, leukemia, multiple myeloma) or therapy (e.g., immunosuppressants, chemotherapy, radiation, steroids [above Cushing threshold]) liver cirrhosis (any Child-Pugh class) body mass index ≥30 kg m-2 history of smoking within two years of surgery age ≥65 years expected anesthesia duration ≥180 minutes B-type natriuretic peptide (BNP) >80 ng/L or N-terminal B-type natriuretic peptide (NT-proBNP) >200 ng/L within the last 6 months Exclusion Criteria: emergency surgery planned surgery: nephrectomy, liver or kidney transplantation surgery status post transplantation of kidney, liver, heart, or lung sepsis (according to current Sepsis-3 definition) American Society of Anesthesiologists physical status classification V or VI pregnancy impossibility of preoperative baseline cardiac index assessment using bioreactance impossibility to perform cardiac index monitoring using the Starling Fluid Management System (Baxter, Deerfield, IL, USA) current participation in another clinical trial or treatment with a similar biological mechanism or primary outcome measure