Study design

This is a monocentric, prospective, open-label, randomised study.

Study population

The inclusion criteria will be:

Patients aged more than 18 years old.

With a vs exposed to NE for at least 4 hours within 48 hours of ICU admission.

After a scheduled cardiac surgery under CPB (coronary artery bypass grafting, valve replacement, ascending aorta replacement or combined surgery (valve and bypass grafting)).

To be entitled to the French national health service (Sécurité Sociale).

Preoperative signature for the consent to participate in the study.

The exclusion criteria will be:

Permanent arrhythmia (atrial fibrillation, flutter or frequent atrial extrasystoles).

Treatment with dobutamine, epinephrine or vasopressin analogue.

Patients with preoperative chronic end-stage renal failure who require postoperative extrarenal purification.

Pregnancy.

The patient is dependent on an internal or external pacemaker.

Hypothermia <36°C.

Patient under mechanical circulatory assistance after cardiac surgery.

Active postoperative bleeding.

Inclusion in another study within the last 30 days.

Patient under guardianship or curatorship.

Study protocolRandomisation

Randomisation will be conducted by the physician in the cardiac, thoracic, vascular and respiratory ICU (CTVR-ICU) once the patient meets the inclusion criteria. Patients will be randomised into two parallel open-label groups using a minimisation algorithm with two strata: Euroscore II and the NE dose at inclusion. The randomisation process will be executed by a data manager using Ennov Clinical software. The patient will be allocated to either the '’sandard group’ or the ‘intervention group’ (see figure 1).

Figure 1

CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials.

Standard care in both groups

In both groups, the conditions for administering NE, such as dilution, infusion rate and NE relay, will follow the local protocol dedicated to patients with postoperative vs in our ICU at Amiens University Hospital and remain consistent with the practices observed beyond the scope of this research study.

In each group and following randomisation, all patients will have an Acumen IQ device connected to either the radial or femoral arterial catheter at the discretion of the clinician in charge. The arterial catheter will be inserted in the operating room under general anaesthesia as part of cardiac surgery procedure. The Acumen IQ device will be linked to the HemoSphere monitor platform (Edwards Lifesciences) to collect all haemodynamic measurements for assessing primary and secondary endpoints. Each nurse intervention (adjustment of NE doses or administration of fluids) is electronically recorded in our healthcare system software and in the HemoSphere monitor. In the standard group, HPI value will not be available on the HemoSphere monitor screen, but the values will be recorded throughout the entire duration of the research protocol.

During the study protocol, in the event of haemodynamic deterioration, all patients will undergo an echocardiographic evaluation to detect any surgical complications and to assess the haemodynamic status. The preload dependency will be evaluated through a passive leg-raising test.12 If the test yields a positive result with a stroke volume variation >15% on the Acumen IQ monitoring, the patient will receive fluid resuscitation with crystalloids or colloids. In case of a negative result, the attending physician may increase NE or introduce a new catecholamine based on the haemodynamic assessment. The research protocol’s duration for each patient is 72 hours. Beyond this time frame, if the administration of NE persists, it will be categorised as an NE weaning failure.

Intervention group

In the intervention group, the weaning of NE will be guided by the HPI and MAP provided by the Acumen IQ (figure 2A) device and the HemoSphere monitor (figure 2B).

Figure 2

(A) The Acumen IQ device, integrated with the arterial catheter. (B) Continuous monitoring and collection of haemodynamic parameters via the HemoSphere monitor.

During each clinical round conducted, which occurs every 2 hours, the nurse may gradually reduce the NE infusion by 0.01 µ/kg/min if the MAP is ≥65 mm Hg and the HPI is <80%. The HPI value will be an average calculated over 10 min and provided by the HemoSphere monitor. Following each step of NE weaning, there will be a 10 min monitoring period before proceeding to the next step. The maximum allowable decrease during the nurse’s round is 0.03 µ/kg/min of NE. If arterial hypotension occurs during these weaning steps, the nurse may increase NE by 0.01 µ/kg/min (figure 3A).

Figure 3

Protocol steps of the intervention group (A) and the standard group (B). HPI, Hypotension Prediction Index; MAP, mean arterial pressure; NE, norepinephrine.

Standard group

In the standard group, the weaning process of NE will be guided by the MAP provided by the Acumen IQ device and the HemoSphere monitor. HPI function of the Acumen IQ device will be disabled on the HemoSphere screen, but HPI values will be recorded alongside other haemodynamic parameters. During each clinical round conducted by the nurse, which occurs every 2 hours, the nurse may gradually reduce NE infusion by 0.01 µ/kg/min if the MAP is ≥65 mm Hg. Following each step of NE weaning, there will be a 10 min monitoring period before proceeding to the next step. The maximum allowable decrease during the nurse’s round is 0.03 µ/kg/min of NE. If arterial hypotension occurs during these weaning steps, the nurse may increase NE by 0.01 µ/kg/min (figure 3B).

Outcome measuresPrimary endpoint

The endpoints and definitions are presented in table 1.

Table 1

Endpoints and definitions

The primary endpoint is comparing the duration of NE administration between the two groups. The duration will be defined as the difference in time between the beginning of the study (day 0) and the end of the study protocol (day 3).

Secondary endpoints

The secondary endpoints encompass several aspects, including the number of failures in the NE weaning protocol and the prevalence, frequency and duration of hypotensive episodes monitored via the Acumen IQ device. Additionally, we aim to assess the total amount of NE administered during the research protocol. Cumulative diuresis and volume of crystalloids, colloids or blood products administrated will also be evaluated during the protocol from day 0 to day 3 and when NE weaning is deemed successful. Furthermore, we will examine the incidence of postoperative complications as defined by the European Society of Anesthesia and Resuscitation, which includes neurological, respiratory, cardiovascular, renal, digestive, haemorrhagic and infectious complications. Other outcomes to be studied will encompass the length of stay in the ICU and in the hospital and all-cause mortality at day 30.

Data collection and outcome definition

The following data will be collected: age (years), gender, body mass index (kg/m²), medical history (coronary disease, peripheral vascular disease, stroke, smoking, diabetes, dyslipidaemia, chronic obstructive pulmonary disease, logistic EuroSCORE II, hypertension, chronic kidney disease, usual medication, surgery type (valve replacement, coronary bypass graft or combined surgery), preoperative left ventricular ejection fraction, baseline haemoglobin, duration of CPB and aortic clamp, intraoperative transfusion and cumulative dose of NE.

After CPB and until the conclusion of the research protocol, the Acumen IQ device will record the following data: systolic arterial pressure, diastolic arterial pressure, MAP, heart rate, cardiac output, stroke volume, dynamic elastance, systolic slope (dP/dT), dynamic arterial elastance (Eadyn), stroke volume variation, systemic vascular resistance and pulse pressure variation.

The following biological data will be collected after CPB and during the research protocol: arterial blood gas variables (pH, PaO2, PaCO2, lactate, HCO3), ScVO2 (%), SOFA score, NE dose and biological variables (creatinine, aspartate aminotransferase, alanine aminotransferase, prothrombin time, platelet count, cardiac troponin, myoglobin).

After CPB and at the end of the research protocol, transthoracic echocardiography will be performed and the following data will be collected: left ventricular ejection fraction, parameters of diastolic function, paravalvular leak, size and volume of cardiac chambers, parameters of right systolic function, size and collapsibility of the inferior vena cava and the presence of pericardial effusion.

The primary endpoint will be assessed when the NE weaning protocol is considered successful or at the end of the research protocol (72 hours after randomisation). The secondary endpoints will be assessed at 30 days. Any clinical adverse events will be documented and reported in the electronic case report forms (eCRFs).

Standard definitions of postoperative outcomes established by the European Society of Anesthesia13 will be used. Cardiac arrest is defined as the cessation of mechanical cardiac activity, confirmed by the absence of signs of circulation. Stroke is defined as an embolic, thrombotic or haemorrhagic cerebral event resulting in persistent motor, sensory or cognitive dysfunction (eg, hemiplegia, hemiparesis, aphasia, sensory deficits, impaired memory), as diagnosed through cerebral CT scanning. Acute kidney injury (AKI) follows the Kidney Disease Improving Global Outcomes criteria, characterised by an increase in serum creatinine of over 27 µmol/L within 48 hours or a diuresis rate lower than 0.5 mL/kg/hour. Myocardial injury is diagnosed based on specific clinical presentation, serial changes in the 12-lead ECG indicative of infarction and an increase in cardiac troponin levels, with at least one value exceeding the 99th percentile of the upper reference limit. Mesenteric ischaemia is diagnosed through imaging or exploratory laparotomy while ischaemic colitis is confirmed via gastrointestinal endoscopy or exploratory laparotomy. Mediastinitis was defined by CT imaging and bacterial documentation. The length of stay in ICU and in hospital (in days) and all-cause mortality will be assessed at the 30-day mark.

Intention-to-treat analysis

Patients experiencing significant clinical adverse events will be analysed according to the group they were initially assigned to (standard or interventional group) by the intention-to-treat principle.

Statistical method and sample size calculation

For the primary endpoint, the null hypothesis (the duration of NE administration is the same between the two groups) will be rejected in favour of the alternative hypothesis (there is a difference) using an independent samples t-test (or Mann-Whitney test depending on the normality of the data) with a two-tailed alpha level of 5%. An analysis of covariance model will validate the difference between the two groups after adjusting for Euroscore II and the NE dose at randomisation. An analysis of variance tests for repeated haemodynamic measures will be used for the secondary endpoints. The number of failures in the weaning NE protocol, postoperative complications and mortality rate will be compared using a χ2 test. The total dose of NE, cumulative diuresis, fluids administered during the NE weaning protocol, ICU and hospital stay will be compared using a Student’s t-test. (or the Mann-Whitney test, depending on the normality of the data. A p value of 0.05 will be considered significant. No interim analysis is planned in the trial.

Sample size calculation

According to a previous study, the SD of the duration of NE administration in patients with vs postcardiac surgery was 6 hours.14 Therefore, to demonstrate a difference of 3 hours between the two groups, it is necessary to include 128 patients. These calculations were performed with a two-tailed alpha level of 5% and a power of 80%. Considering that 10% of patients may not be evaluable for the primary criterion, 142 patients will be included. Amiens University Hospital annually conducts approximately 550 cardiac surgery procedures with on-pump CPB surgery. A recent study conducted at our centre revealed an incidence of 30% of vs following cardiac surgery. Assuming that 50% of vs cases will meet eligibility, the criteria suggest a potential enrolment of 82 patients annually. Considering possible exclusions due to vacations and operating room closures, we anticipate a total enrollment period of 24 months, with a target of 142 patients (71 patients in each group—standard and interventional).