The exploration of perioperative hypotension subtypes: a prospective, single cohort, observational pilot study

Background Hypotension is a risk factor for postoperative complications, but evidence from randomized trials does not support that a higher blood pressure target always leads to optimized outcomes. The heterogeneity of underlying hemodynamics during hypotension may contribute to these contradictory results. Exploring the subtypes of hypotension can enable optimal management of intraoperative hypotension. Methods This is a prospective, observational pilot study. Patients who were ≥ 45 years old and scheduled to undergo moderate-to-high-risk noncardiac surgery were enrolled in this study. The primary objective of this pilot study was to investigate the frequency and distribution of perioperative hypotension and its subtypes (hypotension with or without cardiac output reduction). The exposure of hypotension and its subtypes in patients with and without myocardial or acute kidney injury were also explored. Results Sixty patients were included in the analysis. 83% (50/60) of the patients experienced perioperative hypotension. The median duration of hypotension for each patient was 8.0 [interquartile range, 3.1–23.3] minutes. Reduced cardiac output was present during 77% of the hypotension duration. Patients suffering from postoperative myocardial or acute kidney injury displayed longer duration and more extensive exposure in all hypotension subtypes. However, the percentage of different hypotension subtypes did not differ in patients with or without postoperative myocardial or acute kidney injury. Conclusion Perioperative hypotension was frequently accompanied by cardiac output reduction in moderate-to-high-risk noncardiac surgical patients. However, due to the pilot nature of this study, the relationship between hypotension subtypes and postoperative myocardial or acute kidney injury still needs further exploration. Clinical trial registration https://www.chictr.org.cn/showprojEN.html?proj=134260, CTR2200055929.


Background
3][4] Hemodynamic instability is an important characteristic of surgical patients, and varying degrees of hypotension are common during anesthesia and surgery.Hypotension can decrease organ perfusion pressure and then affect organ perfusion, leading to organ or tissue ischemia. 2However, there were still some studies that suggested no association between hypotension and adverse outcomes. 14,15[18] These contradictory findings can be attributed to many reasons, among which the heterogeneity of hypotension itself may be an important issue.Blood pressure is the result of orderly integrations of multiple hemodynamic elements.Cardiac output and systemic vascular resistance are the two leading determinants.However, capturing advanced hemodynamic parameters, such as cardiac output requires special devices.The complexity and costs of these devices limit their routine use in clinical practice.Therefore, although previous retrospective studies are based on large-sample cohorts, the information related to blood flow or organ perfusion is still lacking.
Researchers have recognized the heterogeneity of hypotension in recent years. [19]Hypotension does not always lead to organ hypoperfusion.It may not affect or may even increase organ perfusion, depending on the relative changes between the perfusion pressure and the regional vascular resistance and pressure autoregulation. [19]Therefore, hypotension may be classified as different subtypes based on the hemodynamic status, pathophysiological mechanisms, and impact on organ perfusion.However, studies investigating the frequency and distribution of hypotension subtypes were lacking, and the association between different hypotension subtypes and postoperative organ injuries is also unknown.Clarifying the characteristics of different types of hypotension can help us better understand the mechanism of hypotension and the main reasons causing hypotension-related organ injury after surgery.This study will investigate the frequency and distribution of different subtypes of hypotension in the perioperative setting, explore the association between different subtypes of hypotension and organ injuries, and finally, find more optimized strategies for perioperative blood pressure management.

Study Objectives
1. Investigate the frequency of hypotension during noncardiac surgery in our institute.2. Describe the pattern and distribution of hypotension subtypes during noncardiac surgery.3. Investigate the incidence of myocardial injury and acute kidney injury after noncardiac surgery in our institute.4. Explore the association between different hypotension subtypes and organ injuries.

Study Design
This is a prospective, single cohort, observational pilot study.Patients undergoing noncardiac surgery at the First Affiliated Hospital, Sun Yat-sen University, will be enrolled in the study from October 2021 to February 2022.
The exclusion criteria are: 1) participating in another interventional study; 2) receiving low-risk surgery only (for example, superficial surgery, breast surgery, thyroid surgery, minor plastic surgery, transurethral resection of the prostate); 3) confirmed to be pregnant and/or nursing mothers; 4) emergency surgery; 5) having severe comorbidities (clinically important intra-cardiac shunts, aortic stenosis with valve area ≤ 1.5 cm 2 , moderate to severe aortic regurgitation, moderate to severe mitral regurgitation, moderate to severe mitral stenosis, persistent atrial fibrillation, acute congestive heart failure); 6) previously receiving heart valve surgery, coronary artery bypass grafting, percutaneous coronary intervention, pacemaker implantation, or ICD implantation; 7) patient in whom an intraoperative mean arterial pressure target will be <65 mmHg (including controlled hypotension); 8) with an intra-aortic balloon pump (IABP) or ventricular assist device(s); 9) requiring multiple vasoactive agents and known diagnosis of ongoing active sepsis.

Study Method
Before recruitment of any subjects into the study, written approval of the protocol and informed consent will be obtained from the Institutional Review Board (IRB).

Subject enrollment, informed consent, and subject identification
The primary investigator will review the subject's medical records for eligibility.Once the potential eligibility has been determined, the study will be discussed with the subject, and interest in study participation will be determined.Potential subjects will be fully informed of the study's purpose and nature, including potential risks and benefits.Subjects who voluntarily agree to participate in the trial will be asked to sign and date the informed consent form (ICF).The ICF will explain the study to the subject in lay terms and inform the subject that they may withdraw from the study at any time and for any reason.The potential study participant must sign the ICF before the subject undergoes the planned surgical intervention.A copy of the signed and dated ICF will be provided to the subject.
Each screened subject will be provided a sequential research ID.The research ID number will be recorded on all study documents and link the study documents to the subject's name and medical records.The subject's name should not be recorded on any study document other than the informed consent form to maintain confidentiality.There are no follow-up requirements for subjects who withdraw from the study before 24-hour after surgery.These subjects will also not be counted toward the eligible subjects enrolled in the trial.

Perioperative monitoring
All patients will receive routine monitoring, including electrocardiography, pulse oximetry, invasive/noninvasive blood pressure, and end-tidal carbon dioxide.In addition, patients will receive an electroencephalogram monitor (Narcotrend®; MonitorTechnik, Bad Bramstedt, Germany) and a hemodynamic monitor (CNAP®; CNSystems Medizintechnik GmbH, Graz, Austria).The finger cuff of the CNAP® monitor will be placed on the hand, while the cuff used for noninvasive blood pressure measurement was placed on the upper arm for calibration.If the patient receives an arterial line, the finger cuff will be placed on the side contralateral to the arterial line.A research laptop will be used to capture all real-time data.The monitoring and data recording will start before anesthesia induction and stop 10-15 minutes after extubation.

Blood sampling and data collection
Venous blood samples will be drawn from each patient at four time points: 1) postoperative 24hour, 2) postoperative 48-hour, 3) postoperative 72-hour, and 4) postoperative 7-day or the last day before the patient's hospital discharge.The concentration of serum troponin T, troponin I, and creatinine will be determined by a researcher who will not involve in the patient care.

Sample size calculation
This is the first study exploring the frequency and distribution of different hypotension subtypes during surgery, and there is no reference for the rates of hypotension subtypes.Therefore, this study should be regarded as a pilot study.According to current guidelines for sample size estimation for pilot studies [20] and the surgical volume of our hospital, we plan to enroll 60 patients.

Statistical analysis plan
The hypotension will be classified into different subtypes depends on whether the cardiac output or systemic vascular resistance decreases.
1. Describe the distribution of perioperative hypotension subtypes during noncardiac surgery by presenting and visualizing the frequency and tendency; 2. Describe the hypotension and hypotension subtypes stratified based on different surgical types, surgical stages, and populations; 3. Describe the incidence of myocardial injury and acute kidney injury after noncardiac surgery in our institute; 4. Explore the association between different hypotension subtypes (types and durations) and postoperative troponin level, creatinine level, rate of myocardial injury, and rate of acute kidney injury, based on linear regression or logistic regression.Multivariable analysis and propensity-score matching will be used to control for confounders.

Bias, quality control, and risk
The data collection process will be done independently by two researchers to ensure data accuracy.
A quality control project (dealing with missing and abnormal data) will be performed prior to the analysis of perioperative monitoring data.A research training will be conducted for all research staffs before data acquisition to ensure consistency.