# Epidemiology, risk factors and outcomes of norepinephrine use in cardiac surgery with cardiopulmonary bypass: a multicentric prospective study

Pierre-Grégoire Guinot, Bastien Durand, Emmanuel Besnier, Paul-Michel Mertes, Chloe Bernard, Maxime Nguyen, Vivien Berthoud, Osama Abou-Arab, Bélaïd Bouhemad

► To cite this version:

Pierre-Grégoire Guinot, Bastien Durand, Emmanuel Besnier, Paul-Michel Mertes, Chloe Bernard, et al. Epidemiology, risk factors and outcomes of norepinephrine use in cardiac surgery with cardiopulmonary bypass: a multicentric prospective study. Anaesthesia Critical Care & Pain Medicine, 2023, 42 (3), pp.101200. 10.1016/j.accpm.2023.101200. hal-03992547

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Original Article

# Epidemiology, risk factors and outcomes of norepinephrine use in cardiac surgery with cardiopulmonary bypass: a multicentric prospective study

<figure><img src="image_1.png" /></figure>

Pierre-Grégoire Guinot<sup>a,b,*</sup>, Bastien Durand<sup>a</sup>, Emmanuel Besnier<sup>c</sup>, Paul-Michel Mertes<sup>d</sup>, Chloe Bernard<sup>e</sup>, Maxime Nguyen<sup>a,b</sup>, Vivien Berthoud<sup>a</sup>, Osama Abou-Arab<sup>f</sup>, Belaid Bouhemad<sup>a,b</sup>, Collaborator study group<sup>1</sup>

ARTICLE INFO

Article history:

Available online 8 February 2023

Keywords:

Norepinephrine

Vasopressor

Cardiac surgery

Cardiopulmonary bypass

Shock

Dobutamine

Sepsis

Acute kidney injury

ABSTRACT

**Background:** The present study was designed to describe the prevalence of norepinephrine use, the factors associated with its use, and the incidence of postoperative complications according to norepinephrine use, in patients undergoing cardiac surgery with cardiopulmonary bypass.

**Method:** We performed a prospective, multicenter, observational study in 4 University-affiliated medical-surgical cardiovascular units. We analyzed all patients treated with cardiac surgery after excluding pre-ECMO surgery, LVAD implantation, heart transplantation and intra-operative hemorrhage.

**Results:** Of 9316 patients screened during the study period, 2862 were included and 2510 were analyzed. Among them, 1549 (61%) were treated with norepinephrine with a median maximal dose of 0.11 [0.06–0.2] µg.kg⁻<fnref n="1" />.min⁻<fnref n="1" /> and a median duration of 10 h [2–24]. Norepinephrine was most often started in the operating room before cardiopulmonary bypass. The multiple regression logistic analysis identified several modifiable (haematocrit, maintenance of beta-blocker, cardiopulmonary bypass time, glucose-insulin-potassium, Custodiol cardioplegia, Delnido cardioplegia, and fibrinogen transfusion) and non-modifiable factors (age, ASA score, chronic high blood pressure, coronary disease, dyslipidemia, right ventricular dysfunction, left ventricular dysfunction, active endocarditis, and valvular aortic surgery) associated with norepinephrine use. Mortality, morbidity (neurological and renal complications, death) and length of stay in the ICU were higher in patients treated with norepinephrine.

**Conclusion:** Norepinephrine is often used in cardiac surgical patients but for <24 h with a low dose. Many preoperative and surgical factors are associated with norepinephrine use. Patients supported by norepinephrine have a higher incidence of major postoperative events.

© 2023 The Author(s). Published by Elsevier Masson SAS on behalf of Société française d'anesthésie et de réanimation (Sfar). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup>Department of Anaesthesiology and Critical Care Medicine, Dijon University Medical Centre, 21000 Dijon, France</footnote>

<footnote><sup>b</sup>University of Burgundy and Franche-Comté, LNC UMR1231, F-21000 Dijon, France</footnote>

<footnote><sup>c</sup>Department of Anaesthesiology and Critical Care Medicine, Rouen University Medical Centre, 76000 Rouen, France</footnote>

<footnote><sup>d</sup>Department of Anaesthesiology and Critical Care Medicine, Strasbourg University Medical Centre, Strasbourg, France</footnote>

<footnote><sup>e</sup>Department of Cardiac Surgery, Dijon University Medical Centre, 21000 Dijon, France</footnote>

<footnote><sup>f</sup>Department of Anaesthesiology and Critical Care Medicine, Amiens University Medical Centre, 80000 Amiens, France</footnote>

<footnote>Abbreviations: AKI, acute kidney injury; ECMO, extra-corporeal membrane oxygenation; LVEF, left ventricular ejection function; CS, post-cardiotomy shock.</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: guinotpierreregnoire@gmail.com (P.-G. Guinot).</footnote>

<footnote n="1">¹ The collaborators are listed in Appendix.</footnote>
Original Article

# Epidemiology, risk factors and outcomes of norepinephrine use in cardiac surgery with cardiopulmonary bypass: a multicentric prospective study

<figure><img src="image_2.png" /></figure>

Pierre-Grégoire Guinot<sup>a,b,*</sup>, Bastien Durand<sup>a</sup>, Emmanuel Besnier<sup>c</sup>, Paul-Michel Mertes<sup>d</sup>, Chloe Bernard<sup>e</sup>, Maxime Nguyen<sup>a,b</sup>, Vivien Berthoud<sup>a</sup>, Osama Abou-Arab<sup>f</sup>, Belaid Bouhemad<sup>a,b</sup>, Collaborator study group<sup>1</sup>

ARTICLE INFO

Article history:

Available online 8 February 2023

Keywords:

Norepinephrine

Vasopressor

Cardiac surgery

Cardiopulmonary bypass

Shock

Dobutamine

Sepsis

Acute kidney injury

ABSTRACT

**Background:** The present study was designed to describe the prevalence of norepinephrine use, the factors associated with its use, and the incidence of postoperative complications according to norepinephrine use, in patients undergoing cardiac surgery with cardiopulmonary bypass.

**Method:** We performed a prospective, multicenter, observational study in 4 University-affiliated medical-surgical cardiovascular units. We analyzed all patients treated with cardiac surgery after excluding pre-ECMO surgery, LVAD implantation, heart transplantation and intra-operative hemorrhage.

**Results:** Of 9316 patients screened during the study period, 2862 were included and 2510 were analyzed. Among them, 1549 (61%) were treated with norepinephrine with a median maximal dose of 0.11 [0.06–0.2] µg.kg⁻<fnref n="1" />.min⁻<fnref n="1" /> and a median duration of 10 h [2–24]. Norepinephrine was most often started in the operating room before cardiopulmonary bypass. The multiple regression logistic analysis identified several modifiable (haematocrit, maintenance of beta-blocker, cardiopulmonary bypass time, glucose-insulin-potassium, Custodiol cardioplegia, Delnido cardioplegia, and fibrinogen transfusion) and non-modifiable factors (age, ASA score, chronic high blood pressure, coronary disease, dyslipidemia, right ventricular dysfunction, left ventricular dysfunction, active endocarditis, and valvular aortic surgery) associated with norepinephrine use. Mortality, morbidity (neurological and renal complications, death) and length of stay in the ICU were higher in patients treated with norepinephrine.

**Conclusion:** Norepinephrine is often used in cardiac surgical patients but for <24 h with a low dose. Many preoperative and surgical factors are associated with norepinephrine use. Patients supported by norepinephrine have a higher incidence of major postoperative events.

© 2023 The Author(s). Published by Elsevier Masson SAS on behalf of Société française d'anesthésie et de réanimation (Sfar). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup>Department of Anaesthesiology and Critical Care Medicine, Dijon University Medical Centre, 21000 Dijon, France</footnote>

<footnote><sup>b</sup>University of Burgundy and Franche-Comté, LNC UMR1231, F-21000 Dijon, France</footnote>

<footnote><sup>c</sup>Department of Anaesthesiology and Critical Care Medicine, Rouen University Medical Centre, 76000 Rouen, France</footnote>

<footnote><sup>d</sup>Department of Anaesthesiology and Critical Care Medicine, Strasbourg University Medical Centre, Strasbourg, France</footnote>

<footnote><sup>e</sup>Department of Cardiac Surgery, Dijon University Medical Centre, 21000 Dijon, France</footnote>

<footnote><sup>f</sup>Department of Anaesthesiology and Critical Care Medicine, Amiens University Medical Centre, 80000 Amiens, France</footnote>

<footnote>Abbreviations: AKI, acute kidney injury; ECMO, extra-corporeal membrane oxygenation; LVEF, left ventricular ejection function; CS, post-cardiotomy shock.</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: guinotpierreregireoire@gmail.com (P.-G. Guinot).</footnote>

<footnote n="1">¹ The collaborators are listed in Appendix.</footnote>
## Introduction

Cardiac surgery is associated with hemodynamic disturbance with arterial hypotension in relation to low cardiac output syndrome and/or alteration in vasomotor tone [1,2]. Vasomotor tone alteration is usually assimilated to the vasoplegic syndrome that is treated with vasopressors [2]. The incidence of vasoplegic syndrome is wide depending on the definition used but remains a daily problem in cardiac surgery, since it is associated with an increase in length of stay in the intensive care unit, and hospitalization costs [2]. Studies have evaluated the epidemiology of vasoplegic syndrome but most of these studies are old, retrospective, single-centred with a low number of patients, and use different definitions of the vasoplegic syndrome [2-5]. In recent years, the concept of hemodynamic optimization of high-risk surgical patients evolved towards more active care to reduce complication risk. Thus, patients are more treated with vasopressors than in the past, to meet more stringent hemodynamic targets. A recent expert consensus has strongly recommended using norepinephrine (NE) as first-line vasopressor therapy in cardiac surgery [6]. NE use in cardiac surgery, the factors associated with its use, and the incidence of complications were not specifically studied yet. Most of the published studies have focused on vasoplegic syndrome or a comparison between catecholaminergic and non-catecholaminergic vasopressors [7-9].

Regarding the evolution of cardiac surgical technique, anaesthesia, and perioperative hemodynamic treatment, we hypothesized that NE may be the main and the most frequent vasopressor used in patients undergoing cardiac surgery with cardiopulmonary bypass. Patients supported with NE may represent a high-risk population with a high incidence of postoperative complications. In absence of data, we designed the present study to describe the prevalence of NE use, the factors associated with its use, and the incidence of complications in patients supported by NE.

## Materials and methods

### Study design

This was a multicenter observational prospective study approved by the French ethical committee (Comité De Protection Des Personnes Sud Mediterranee I, 2017-A01324-49, Chairman: Pr Y. JAMMES) for human subjects [10]. The study was conducted in the anesthesia and critical care cardiac surgical department of four university-affiliated tertiary hospitals from 2017 to 2021. All patients have received a written document for research purposes and gave their consent prior to participating. The study design adheres to the Medical Research Involving Human Subject Act requirements and the Declaration of Helsinki. The reporting of this study complied with STROBE guidelines.

### Study population

The main inclusion criteria were as follows: patients aged ≥18 years who underwent cardiac surgery with the use of cardiopulmonary bypass (CPB). The main non-inclusion criteria were off-pump cardiac surgery, pre-operative VA-ECMO, left ventricular assist device, and heart transplantation. Other exclusion criteria were incomplete data (no missing data on variables assessed), and intra-operative hemorrhagic shock (intra-operative excessive bleeding that necessitates ≥ three units of red blood cell transfusion, or that delayed sternal closure [11]). For included patients, NE was noted when it was used in the operating room and/or in the intensive care unit (ICU).

## Intraoperative and ICU management

Anesthesia, CPB procedures and post-operative management were left at the physicians' discretion, as previously described [12,13]. Circulatory support was guided to achieve predefined clinical endpoints: mean arterial pressure ≥ 65 mmHg, cardiac index ≥2.2 L.min⁻¹.m⁻² and urine output ≥0.5 mL⁻¹.kg⁻¹.h⁻¹. Electrocardiogram, pulse oxygen saturation and central venous blood pressure were continuously monitored. Scheduled blood tests included arterial/venous blood gas measurements on admission at ICU, and then several times a day on request by the attending physician. Once hemodynamic stability and normothermia were obtained and blood loss was considered acceptable (<1 mL⁻¹.kg⁻¹.h⁻¹), respiratory weaning was attempted. All patients were managed by a specialized team trained in post-operative cardiac surgery care.

### Data collection

All data were anonymously, consecutively and prospectively recorded using a dedicated, secure, web-based system case report form (Ennov clinical software). The following variables were recorded: age, gender, body weight, height, personal medical history, personal medications, ASA score, EuroSCORE 2, preoperative left ventricular ejection fraction, right ventricular dysfunction, pulmonary artery pressure, emergency, redo surgery, number of procedure, type of surgery, type of cardioplegia, hypothermia (defined as the core temperature below 35°C), amount of intraoperative fluid, duration of anesthesia, duration of CPB, duration of aortic clamping, the need for intraoperative blood transfusion, acid tranexamic/aprotinin use, opioid/non-opioid anesthesia, dobutamine (duration, maximum posology), epinephrine (duration, maximum posology), creatinine value, time to extubation (hours), any occurrence of complications during the stay in the ICU or the hospital, and the length of stay (LOS) in the ICU and the hospital.

### Endpoints and definition of complications

The primary endpoint was the number of patients treated with *tartrate norepinephrine* out of the context of intra-operative haemorrhagic shock. The maximal dose (in µg.kg⁻¹.min⁻¹) used in the operative room and ICU was noted. The duration time was defined as the total time treated with NE from the start of surgery to the end of ICU stays, expressed in hours.

The secondary endpoints were major adverse post-operative events (stroke, delirium, new onset of atrial fibrillation or flutter, low cardiac output syndrome, acute kidney injury (AKI), sepsis, and in-hospital death), total intraoperative fluids administered (ml), total propofol dose (mg.kg⁻¹), opioid use, vasopressor use (number of patients and higher dose), inotrope use (number of patients and higher dose), and total ICU/hospital LOS (in days). Complications were prospectively noted during the ICU and hospital stays. Complications were defined according to the European Perioperative Clinical Outcome definitions: neurological, cardiovascular, acute kidney injury, hemorrhagic, and infectious complications [12,14]. Stroke was defined as an embolic, thrombotic, or hemorrhagic cerebral event with persistent residual motor, sensory, or cognitive dysfunction (e.g., hemiplegia, hemiparesis, aphasia, sensory deficit, impaired memory) diagnosed by brain computed tomography scan. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit. AKI was defined according to kidney disease improving global outcomes (KDIGO) criteria. AKI stage 1 is defined as an increase in serum creatinine (SCr) by ≥0.3 mg.dL⁻¹ or an increase in SCr to ≥1.5
## Introduction

Cardiac surgery is associated with hemodynamic disturbance with arterial hypotension in relation to low cardiac output syndrome and/or alteration in vasomotor tone [1,2]. Vasomotor tone alteration is usually assimilated to the vasoplegic syndrome that is treated with vasopressors [2]. The incidence of vasoplegic syndrome is wide depending on the definition used but remains a daily problem in cardiac surgery, since it is associated with an increase in length of stay in the intensive care unit, and hospitalization costs [2]. Studies have evaluated the epidemiology of vasoplegic syndrome but most of these studies are old, retrospective, single-centred with a low number of patients, and use different definitions of the vasoplegic syndrome [2-5]. In recent years, the concept of hemodynamic optimization of high-risk surgical patients evolved towards more active care to reduce complication risk. Thus, patients are more treated with vasopressors than in the past, to meet more stringent hemodynamic targets. A recent expert consensus has strongly recommended using norepinephrine (NE) as first-line vasopressor therapy in cardiac surgery [6]. NE use in cardiac surgery, the factors associated with its use, and the incidence of complications were not specifically studied yet. Most of the published studies have focused on vasoplegic syndrome or a comparison between catecholaminergic and non-catecholaminergic vasopressors [7-9].

Regarding the evolution of cardiac surgical technique, anaesthesia, and perioperative hemodynamic treatment, we hypothesized that NE may be the main and the most frequent vasopressor used in patients undergoing cardiac surgery with cardiopulmonary bypass. Patients supported with NE may represent a high-risk population with a high incidence of postoperative complications. In absence of data, we designed the present study to describe the prevalence of NE use, the factors associated with its use, and the incidence of complications in patients supported by NE.

## Materials and methods

### Study design

This was a multicenter observational prospective study approved by the French ethical committee (Comité De Protection Des Personnes Sud Mediterranee I, 2017-A01324-49, Chairman: Pr Y. JAMMES) for human subjects [10]. The study was conducted in the anesthesia and critical care cardiac surgical department of four university-affiliated tertiary hospitals from 2017 to 2021. All patients have received a written document for research purposes and gave their consent prior to participating. The study design adheres to the Medical Research Involving Human Subject Act requirements and the Declaration of Helsinki. The reporting of this study complied with STROBE guidelines.

### Study population

The main inclusion criteria were as follows: patients aged ≥18 years who underwent cardiac surgery with the use of cardiopulmonary bypass (CPB). The main non-inclusion criteria were off-pump cardiac surgery, pre-operative VA-ECMO, left ventricular assist device, and heart transplantation. Other exclusion criteria were incomplete data (no missing data on variables assessed), and intra-operative hemorrhagic shock (intra-operative excessive bleeding that necessitates ≥ three units of red blood cell transfusion, or that delayed sternal closure [11]). For included patients, NE was noted when it was used in the operating room and/or in the intensive care unit (ICU).

## Intraoperative and ICU management

Anesthesia, CPB procedures and post-operative management were left at the physicians' discretion, as previously described [12,13]. Circulatory support was guided to achieve predefined clinical endpoints: mean arterial pressure ≥ 65 mmHg, cardiac index ≥2.2 L.min⁻¹.m⁻² and urine output ≥0.5 mL⁻¹.kg⁻¹.h⁻¹. Electrocardiogram, pulse oxygen saturation and central venous blood pressure were continuously monitored. Scheduled blood tests included arterial/venous blood gas measurements on admission at ICU, and then several times a day on request by the attending physician. Once hemodynamic stability and normothermia were obtained and blood loss was considered acceptable (<1 mL⁻¹.kg⁻¹.h⁻¹), respiratory weaning was attempted. All patients were managed by a specialized team trained in post-operative cardiac surgery care.

### Data collection

All data were anonymously, consecutively and prospectively recorded using a dedicated, secure, web-based system case report form (Ennov clinical software). The following variables were recorded: age, gender, body weight, height, personal medical history, personal medications, ASA score, EuroSCORE 2, preoperative left ventricular ejection fraction, right ventricular dysfunction, pulmonary artery pressure, emergency, redo surgery, number of procedure, type of surgery, type of cardioplegia, hypothermia (defined as the core temperature below 35°C), amount of intraoperative fluid, duration of anesthesia, duration of CPB, duration of aortic clamping, the need for intraoperative blood transfusion, acid tranexamic/aprotinin use, opioid/non-opioid anesthesia, dobutamine (duration, maximum posology), epinephrine (duration, maximum posology), creatinine value, time to extubation (hours), any occurrence of complications during the stay in the ICU or the hospital, and the length of stay (LOS) in the ICU and the hospital.

### Endpoints and definition of complications

The primary endpoint was the number of patients treated with *tartrate norepinephrine* out of the context of intra-operative haemorrhagic shock. The maximal dose (in µg.kg⁻¹.min⁻¹) used in the operative room and ICU was noted. The duration time was defined as the total time treated with NE from the start of surgery to the end of ICU stays, expressed in hours.

The secondary endpoints were major adverse post-operative events (stroke, delirium, new onset of atrial fibrillation or flutter, low cardiac output syndrome, acute kidney injury (AKI), sepsis, and in-hospital death), total intraoperative fluids administered (ml), total propofol dose (mg.kg⁻¹), opioid use, vasopressor use (number of patients and higher dose), inotrope use (number of patients and higher dose), and total ICU/hospital LOS (in days). Complications were prospectively noted during the ICU and hospital stays. Complications were defined according to the European Perioperative Clinical Outcome definitions: neurological, cardiovascular, acute kidney injury, hemorrhagic, and infectious complications [12,14]. Stroke was defined as an embolic, thrombotic, or hemorrhagic cerebral event with persistent residual motor, sensory, or cognitive dysfunction (e.g., hemiplegia, hemiparesis, aphasia, sensory deficit, impaired memory) diagnosed by brain computed tomography scan. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit. AKI was defined according to kidney disease improving global outcomes (KDIGO) criteria. AKI stage 1 is defined as an increase in serum creatinine (SCr) by ≥0.3 mg.dL⁻¹ or an increase in SCr to ≥1.5
times baseline, or urine output < 0.5 mL.kg⁻¹.h⁻¹ for 6–12 h. AKI stage 2 is defined as an increase in SCr to ≥2.0–2.9 times the baseline, or urine output < 0.5 mL.kg⁻¹.h⁻¹ for ≥12 h. AKI stage 3 is defined as an SCR of up to 3.0 times the baseline or SCR increased to ≥4.0 mg.dL⁻¹ or the initiation of renal replacement therapy or urine output <0.3 mL.kg⁻¹.h⁻¹ for ≥24 h or anuria for ≥12 h.

To study the association between NE exposure and complications, a composite of post-operative Major Adverse Kidney and Cerebral Events was constructed. The composite score includes stroke, AKI, and death.

Statistical analysis

The trial was designed to describe the use of NE in cardiac surgery with cardiopulmonary bypass and to investigate the

factors associated with its use. According to the literature and guidelines that consider one analysed factor per 10 events, it was decided to include 20 events per analysed factor to obtain a stable model. Thus, it will be possible to include up to 70 factors with a sample size of 2500 patients to analyse the risk factor of NE use. Taking into account the exclusion criteria, the sample size was increased to 3000 patients.

Normality was visually assessed using histograms and interquartile plots. Accordingly, quantitative data are presented as medians [interquartile range], and qualitative data are presented as frequencies and percentages.

A multivariate logistic regression model with a backward process (variables with a p-value of 0.20 were included) was performed. To take into account the effect of the centre, the centre was included in the multivariate logistic regression model. The association between risk factors and NE was evaluated by the odds

Study flow chart

<figure><img src="image_2.png" /><figcaption>Fig. 1. Flow chart diagram of the study.</figcaption></figure>
times baseline, or urine output < 0.5 mL.kg⁻¹.h⁻¹ for 6–12 h. AKI stage 2 is defined as an increase in SCr to ≥2.0–2.9 times the baseline, or urine output < 0.5 mL.kg⁻¹.h⁻¹ for ≥12 h. AKI stage 3 is defined as an SCR of up to 3.0 times the baseline or SCR increased to ≥4.0 mg.dL⁻¹ or the initiation of renal replacement therapy or urine output <0.3 mL.kg⁻¹.h⁻¹ for ≥24 h or anuria for ≥12 h.

To study the association between NE exposure and complications, a composite of post-operative Major Adverse Kidney and Cerebral Events was constructed. The composite score includes stroke, AKI, and death.

Statistical analysis

The trial was designed to describe the use of NE in cardiac surgery with cardiopulmonary bypass and to investigate the

factors associated with its use. According to the literature and guidelines that consider one analysed factor per 10 events, it was decided to include 20 events per analysed factor to obtain a stable model. Thus, it will be possible to include up to 70 factors with a sample size of 2500 patients to analyse the risk factor of NE use. Taking into account the exclusion criteria, the sample size was increased to 3000 patients.

Normality was visually assessed using histograms and interquartile plots. Accordingly, quantitative data are presented as medians [interquartile range], and qualitative data are presented as frequencies and percentages.

A multivariate logistic regression model with a backward process (variables with a p-value of 0.20 were included) was performed. To take into account the effect of the centre, the centre was included in the multivariate logistic regression model. The association between risk factors and NE was evaluated by the odds

Study flow chart

<figure><img src="image_3.png" /><figcaption>Fig. 1. Flow chart diagram of the study.</figcaption></figure>
ratio (OR) and its [95% confidence interval]. Calibration of the final logistic model was assessed using the Hosmer–Lemeshow statistic.

We performed a propensity score matching to analyse the association between NE exposure and Major Adverse Renal and Cerebral Events. The propensity matching was performed as recommended [15], using a nearest-neighbour algorithm with 1:1 matching without replacement, and a calliper distance of <0.2 of the standard deviation of the logit of the propensity score, to reduce the influence of potential confounders between the two groups. The adequacy of covariates balance in the matched sample was assessed using absolute standardized mean differences (mean difference expressed in units of SMD). Covariates were selected considering the already validated prognostic scores in the perioperative setting (ASA score) and surgical setting (EuroSCORE II), and secondly, the choice of covariate was based on clinically pertinent and non-redundant variables with a higher baseline disequilibrium between the two groups. In the matched cohort, the comparison regarding the primary endpoint between the two groups of treatment was performed using the McNemar test. The treatment effect was evaluated using logistical regression. The comparison of the secondary endpoint used the McNemar test or the Wilcoxon signed-rank test. Because we tested multiple outcomes, the threshold for statistical significance was corrected by using a Bonferroni correction and set at *p* < 0.01 (0.008 divided by 6, the number of assessed outcomes). All analyses were performed using R software version 3.4.4 (R Foundation for Statistical Computing, Austria). We used the “Matchlt” package for propensity score matching. The threshold for statistical significance was set at *p* < 0.05.

# Results

## General population

Of the 9316 patients included during the study period, 2541 were analyzed due to the non-inclusion of 138 patients because of incomplete data and 321 patients who had intraoperative hemorrhage (Fig. 1). In the overall study population, the median age was 69 years [61–74] (males: n = 1928, 77%), and the median EuroSCORE 2 was 1.8 [0.9–3.5]. Most surgeries were valve surgery (aortic, mitral, tricuspid), coronary artery bypass graft surgery, and combined surgery (Table 1, Supplementary Tables 1 and 2).

## Patients treated with norepinephrine

Of the 2541 patients, 1549 (61%) were treated with NE with a median maximal dose of 0.11 [0.06–0.2] µg.kg⁻¹.min⁻¹, and a median duration of 10 h [2–24] (Table 2). Only 25% of patients were treated for >24 h with NE. A weak correlation was demonstrated between duration and dose of NE (r = 0.474, *p* = 0.0001). Apart from the NE-treated cohort, NE was started after anesthesia induction for 889 patients (57%), during the cardiopulmonary bypass for 984 (64%) patients, and after cardiopulmonary bypass weaning for 1227 (82%) patients. NE was introduced in the ICU for 322 (18%) patients (Table 2). None were treated with vasopressin and 315 (12%) patients were treated with dobutamine.

Patients treated with NE were older with higher Euroscore 2 and ASA scores, had a higher prevalence of cardiovascular, renal and respiratory comorbidities, were more often treated with beta-blocker agents, diuretics, and angiotensin-converting enzyme inhibitor (Table 1, Supplementary Tables 1 and 2). They had more emergency surgery, endocarditis, redo surgery, coronary artery bypass graft surgery, mixed surgery, longer cardiopulmonary

bypass time, higher use of Custodiol and Delnido cardioplegia, hypothermia, opioid-free anesthesia, fibrinogen and red blood cell transfusions (Supplementary Table 2).

## Factors associated with norepinephrine use

Univariate analysis identified several variables that were included in the multivariate logistic regression (Supplementary Table 3). Multivariate analysis demonstrated an association between NE use and age, ASA score, chronic high blood pressure, coronary disease, dyslipidemia, right ventricular dysfunction, LVEF, hematocrit, maintenance of beta-blocker, active endocarditis, valvular aortic surgery, cardiopulmonary bypass time, Glucose-insulin-potassium use, Custodiol cardioplegia, Delnido cardioplegia, and operative fibrinogen transfusion (Supplementary Table 3, Fig. 2). The Hosmer and Lemeshow test were 9.5 (*p* = 0.37). The AUC of the model was 0.75 [95%CI:0.72–0.76], *p* = 0.0001.

## Incidence of post-operative outcome according to norepinephrine use

Crude analysis demonstrated a worst post-operative course in patients treated with NE because of higher incidence of neurologic, cardiovascular, renal, and septic events and death (Supplementary Table 4). After propensity matching analysis, the use of NE was associated with a higher prevalence of composite scores in relation to a higher incidence of AKI and death (Table 3, Fig. 3). Logistic regression confirms the association between NE exposure and the composite postoperative complications (OR: 2.1 [95%CI: 1.58–3.92], *p* = 0.001). ICU and hospital length of stays were higher in patients treated with NE (Table 3).

# Discussion

Our results may be summarized as follows: (1) NE is often used in cardiac surgery with cardiopulmonary bypass; (2) patients treated with NE have more comorbidities, higher medications, and more complex surgery (3) several factors (modifiable and non-modifiable) were associated with NE use, (4) patients supported by NE have a higher incidence of post-operative complications.

The present study is the first study that analyzes the use of NE from an epidemiology point-of-view in a large prospective multicentric cohort of cardiac surgical patients, out of the context of hemorrhagic shock. NE is often used for a short time (<24 h) and with low posology (<0.1 µg.kg⁻¹.min⁻¹). In >70% of the case, NE was started in the operating room. We observed a higher prevalence of NE use than that previously reported in studies evaluating vasoplegia (between 10 and 45%) [2,3,5]. Contrary to these previous studies, we observed a switch from a higher rate of NE use to phenylephrine use. The present results are in line with recent expert consensus that recommended NE as a first-line vasopressor agent [6]. A recent study performed in the United States has observed a rate of up to 90% of vasoactive medication in cardiac surgical patients; of these medications, phenylephrine was used in 77%, and NE in 37% of the case [16].

Several factors can explain the high rate of NE use. First, several studies performed in ICU and high-risk surgical patients have demonstrated that NE is easy to use and may better improve tissue perfusion than phenylephrine [17]. Thus, in European countries, there is a switch from phenylephrine to NE, particularly in high-risk surgical populations. Second, the studied population has a higher Euroscore risk and prevalence of comorbidities than what is usually described. NE may be more often initially use as a vasopressor for blood pressure optimization than as a treatment of vasoplegic syndrome *per se*. In this way, NE infusion was started in 50% of the cases after the induction of general anesthesia. Third, as
ratio (OR) and its [95% confidence interval]. Calibration of the final logistic model was assessed using the Hosmer–Lemeshow statistic.

We performed a propensity score matching to analyse the association between NE exposure and Major Adverse Renal and Cerebral Events. The propensity matching was performed as recommended [15], using a nearest-neighbour algorithm with 1:1 matching without replacement, and a calliper distance of <0.2 of the standard deviation of the logit of the propensity score, to reduce the influence of potential confounders between the two groups. The adequacy of covariates balance in the matched sample was assessed using absolute standardized mean differences (mean difference expressed in units of SMD). Covariates were selected considering the already validated prognostic scores in the perioperative setting (ASA score) and surgical setting (EuroSCORE II), and secondly, the choice of covariate was based on clinically pertinent and non-redundant variables with a higher baseline disequilibrium between the two groups. In the matched cohort, the comparison regarding the primary endpoint between the two groups of treatment was performed using the McNemar test. The treatment effect was evaluated using logistical regression. The comparison of the secondary endpoint used the McNemar test or the Wilcoxon signed-rank test. Because we tested multiple outcomes, the threshold for statistical significance was corrected by using a Bonferroni correction and set at *p* < 0.01 (0.008 divided by 6, the number of assessed outcomes). All analyses were performed using R software version 3.4.4 (R Foundation for Statistical Computing, Austria). We used the “Matchlt” package for propensity score matching. The threshold for statistical significance was set at *p* < 0.05.

# Results

## General population

Of the 9316 patients included during the study period, 2541 were analyzed due to the non-inclusion of 138 patients because of incomplete data and 321 patients who had intra-operative hemorrhage (Fig. 1). In the overall study population, the median age was 69 years [61–74] (males: n = 1928, 77%), and the median EuroSCORE 2 was 1.8 [0.9–3.5]. Most surgeries were valve surgery (aortic, mitral, tricuspid), coronary artery bypass graft surgery, and combined surgery (Table 1, Supplementary Tables 1 and 2).

## Patients treated with norepinephrine

Of the 2541 patients, 1549 (61%) were treated with NE with a median maximal dose of 0.11 [0.06–0.2] µg.kg⁻¹.min⁻¹, and a median duration of 10 h [2–24] (Table 2). Only 25% of patients were treated for >24 h with NE. A weak correlation was demonstrated between duration and dose of NE (r = 0.474, *p* = 0.0001). Apart from the NE-treated cohort, NE was started after anesthesia induction for 889 patients (57%), during the cardiopulmonary bypass for 984 (64%) patients, and after cardiopulmonary bypass weaning for 1227 (82%) patients. NE was introduced in the ICU for 322 (18%) patients (Table 2). None were treated with vasopressin and 315 (12%) patients were treated with dobutamine.

Patients treated with NE were older with higher Euroscore 2 and ASA scores, had a higher prevalence of cardiovascular, renal and respiratory comorbidities, were more often treated with beta-blocker agents, diuretics, and angiotensin-converting enzyme inhibitor (Table 1, Supplementary Tables 1 and 2). They had more emergency surgery, endocarditis, redo surgery, coronary artery bypass graft surgery, mixed surgery, longer cardiopulmonary

bypass time, higher use of Custodiol and Delnido cardioplegia, hypothermia, opioid-free anesthesia, fibrinogen and red blood cell transfusions (Supplementary Table 2).

## Factors associated with norepinephrine use

Univariate analysis identified several variables that were included in the multivariate logistic regression (Supplementary Table 3). Multivariate analysis demonstrated an association between NE use and age, ASA score, chronic high blood pressure, coronary disease, dyslipidemia, right ventricular dysfunction, LVEF, hematocrit, maintenance of beta-blocker, active endocarditis, valvular aortic surgery, cardiopulmonary bypass time, Glucose-insulin-potassium use, Custodiol cardioplegia, Delnido cardioplegia, and operative fibrinogen transfusion (Supplementary Table 3, Fig. 2). The Hosmer and Lemeshow test were 9.5 (*p* = 0.37). The AUC of the model was 0.75 [95%CI:0.72–0.76], *p* = 0.0001.

## Incidence of post-operative outcome according to norepinephrine use

Crude analysis demonstrated a worst post-operative course in patients treated with NE because of higher incidence of neurologic, cardiovascular, renal, and septic events and death (Supplementary Table 4). After propensity matching analysis, the use of NE was associated with a higher prevalence of composite scores in relation to a higher incidence of AKI and death (Table 3, Fig. 3). Logistic regression confirms the association between NE exposure and the composite postoperative complications (OR: 2.1 [95%CI: 1.58–3.92], *p* = 0.001). ICU and hospital length of stays were higher in patients treated with NE (Table 3).

# Discussion

Our results may be summarized as follows: (1) NE is often used in cardiac surgery with cardiopulmonary bypass; (2) patients treated with NE have more comorbidities, higher medications, and more complex surgery (3) several factors (modifiable and non-modifiable) were associated with NE use, (4) patients supported by NE have a higher incidence of post-operative complications.

The present study is the first study that analyzes the use of NE from an epidemiology point-of-view in a large prospective multicentric cohort of cardiac surgical patients, out of the context of hemorrhagic shock. NE is often used for a short time (<24 h) and with low posology (<0.1 µg.kg⁻¹.min⁻¹). In >70% of the case, NE was started in the operating room. We observed a higher prevalence of NE use than that previously reported in studies evaluating vasoplegia (between 10 and 45%) [2,3,5]. Contrary to these previous studies, we observed a switch from a higher rate of NE use to phenylephrine use. The present results are in line with recent expert consensus that recommended NE as a first-line vasopressor agent [6]. A recent study performed in the United States has observed a rate of up to 90% of vasoactive medication in cardiac surgical patients; of these medications, phenylephrine was used in 77%, and NE in 37% of the case [16].

Several factors can explain the high rate of NE use. First, several studies performed in ICU and high-risk surgical patients have demonstrated that NE is easy to use and may better improve tissue perfusion than phenylephrine [17]. Thus, in European countries, there is a switch from phenylephrine to NE, particularly in high-risk surgical populations. Second, the studied population has a higher Euroscore risk and prevalence of comorbidities than what is usually described. NE may be more often initially use as a vasopressor for blood pressure optimization than as a treatment of vasoplegic syndrome *per se*. In this way, NE infusion was started in 50% of the cases after the induction of general anesthesia. Third, as
<table><caption>**Table 1**
Demographic, medical history and treatment according to norepinephrine use.</caption><thead><tr><th></th><th>Overall population N = 2541</th><th>Norepinephrine free N = 992</th><th>Norepinephrine N = 1549</th><th>p-value</th></tr></thead><tbody><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td></tr><tr><td>Age (years)</td><td>69 [61,74]</td><td>67 [59,73]</td><td>69 [63,75]</td><td>0.0001</td></tr><tr><td>Gender (male)</td><td>1928 (76)</td><td>749 (76)</td><td>1179 (76)</td><td>0.73</td></tr><tr><td>Body Mass Index (kg.m<sup>-2</sup>)</td><td>27.9 [24.4,30.5]</td><td>26.8 [24,30.1]</td><td>26.8 [24,30.6]</td><td>0.02</td></tr><tr><td>Chronic high blood pressure</td><td>1664 (66)</td><td>634 (64)</td><td>1030 (67)</td><td>0.1</td></tr><tr><td>Coronary disease</td><td>1205 (48)</td><td>387 (39)</td><td>818 (52)</td><td>0.0001</td></tr><tr><td>Atrial fibrillation</td><td>439 (17)</td><td>127 (13)</td><td>312 (20)</td><td>0.0001</td></tr><tr><td>Peripheral arterial disease</td><td>240 (10)</td><td>83 (8)</td><td>157 (10)</td><td>0.14</td></tr><tr><td>Carotid artery stenosis</td><td>136 (5)</td><td>45 (5)</td><td>91 (6)</td><td>0.14</td></tr><tr><td>Stroke</td><td>204 (8)</td><td>58 (6)</td><td>146 (9)</td><td>0.001</td></tr><tr><td>Insulin-dependent diabetes</td><td>179 (7)</td><td>67 (7)</td><td>112 (6)</td><td>0.69</td></tr><tr><td>Non insulin-dependent diabetes</td><td>521 (21)</td><td>198 (20)</td><td>323 (21)</td><td>0.61</td></tr><tr><td>Dyslipidemia</td><td>1134 (45)</td><td>388 (39)</td><td>746 (48)</td><td>0.0001</td></tr><tr><td>Chronic renal failure (eGFR &lt;60 (mL.min<sup>-1</sup>.m<sup>-2</sup>)</td><td>415 (16)</td><td>117 (12)</td><td>298 (19)</td><td>0.0001</td></tr><tr><td>Dialysis</td><td>20 (1)</td><td>2 (0.2)</td><td>18 (1)</td><td>0.01</td></tr><tr><td>Estimated glomerular filtration rate (ml.min<sup>-1</sup>.m<sup>-2</sup>)</td><td>81 [66,97]</td><td>83 [70,99]</td><td>80 [64,96]</td><td>0.001</td></tr><tr><td>Haematocrit (%)</td><td>41.4 [38.3, 44.3]</td><td>42 [39,45.6]</td><td>41 [37.6,44]</td><td>0.001</td></tr><tr><td>Left ventricular ejection fraction (%)</td><td>59 [10]</td><td>60 [10]</td><td>56 [11]</td><td>0.0001</td></tr><tr><td>Right ventricular dysfunction</td><td>95 (4)</td><td>20 (2)</td><td>75 (5)</td><td>0.0001</td></tr><tr><td>Pulmonary artery pressure (mmHg)</td><td>28 [24,32]</td><td>28 [25,35]</td><td>30 [23,40]</td><td>0.0001</td></tr><tr><td>Medications</td><td></td><td></td><td></td><td></td></tr><tr><td>Beta-blockers</td><td>954 (38)</td><td>375 (38)</td><td>579 (37)</td><td>0.0001</td></tr><tr><td>Withdraw on the morning of surgery</td><td>533 (21)</td><td>132 (13)</td><td>401 (26)</td><td></td></tr><tr><td>Calcium channel blockers</td><td>533 (21)</td><td>205 (20)</td><td>328 (21)</td><td>0.76</td></tr><tr><td>Angiotensin-converting enzyme inhibitor</td><td>548 (15)</td><td>182 (16)</td><td>366 (13)</td><td>0.001</td></tr><tr><td>Withdraw 24 h before surgery</td><td>354 (65)</td><td>160 (87)</td><td>194 (53)</td><td></td></tr><tr><td>Amiodarone</td><td>141 (6)</td><td>44 (4)</td><td>97 (6)</td><td>0.05</td></tr><tr><td>Anti-aldosterone</td><td>98 (4)</td><td>27 (3)</td><td>71 (5)</td><td>0.02</td></tr><tr><td>Aspirin</td><td>1333 (53)</td><td>472 (48)</td><td>861 (56)</td><td>0.0001</td></tr><tr><td>Clopidogrel</td><td>207 (8)</td><td>75 (8)</td><td>132 (9)</td><td>0.41</td></tr><tr><td>Vitamin K antagonist</td><td>140 (6)</td><td>38 (4)</td><td>102 (7)</td><td>0.003</td></tr><tr><td>Statin</td><td>1383 (55)</td><td>485 (49)</td><td>898 (58)</td><td>0.0001</td></tr><tr><td>Loop diuretic</td><td>558 (22)</td><td>157 (16)</td><td>401 (26)</td><td>0.001</td></tr><tr><td>Insulin</td><td>179 (7)</td><td>67 (6)</td><td>112 (7)</td><td>0.69</td></tr><tr><td>Metformin</td><td>241 (9)</td><td>92 (9)</td><td>149 (10)</td><td>0.83</td></tr><tr><td>Other antidiabetic drugs</td><td>242 (9)</td><td>93 (9)</td><td>149 (10)</td><td>0.89</td></tr><tr><td>Scores</td><td></td><td></td><td></td><td></td></tr><tr><td>Euroscore 2</td><td>1.8 [1, 3.5]</td><td>1.4 [0.8,2.5]</td><td>2.1 [1.1,4.1]</td><td>0.0001</td></tr><tr><td>American Society Anesthesiology score (ASA)</td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>9 (2)</td><td>7 (1)</td><td>2 (1)</td><td></td></tr><tr><td>2</td><td>235 (10)</td><td>116 (12)</td><td>119 (7)</td><td></td></tr><tr><td>3</td><td>1985 (79)</td><td>793 (79)</td><td>1192 (76)</td><td>0.0001</td></tr><tr><td>4</td><td>297 (12)</td><td>71 (7)</td><td>226 (15)</td><td></td></tr><tr><td>5</td><td>15 (1)</td><td>5 (1)</td><td>10 (1)</td><td></td></tr><tr><td>Type of surgery</td><td></td><td></td><td></td><td></td></tr><tr><td>Urgent</td><td>347 (14)</td><td>77 (8)</td><td>270 (17)</td><td>0.0001</td></tr><tr><td>Preoperative sepsis</td><td>69 (3)</td><td>11 (1)</td><td>58 (4)</td><td>0.0001</td></tr><tr><td>Previous cardiac surgery</td><td>97 (4)</td><td>21 (2)</td><td>76 (5)</td><td>0.0001</td></tr><tr><td>Active endocarditis</td><td>65 (3)</td><td>8 (1)</td><td>57 (4)</td><td>0.0001</td></tr><tr><td>Valvular surgery</td><td>1453 (57)</td><td>629 (63)</td><td>824 (53)</td><td>0.0001</td></tr><tr><td>Mitral</td><td>435 (17)</td><td>142 (14)</td><td>293 (19)</td><td>0.003</td></tr><tr><td>Aortic</td><td>1065 (42)</td><td>503 (51)</td><td>562 (36)</td><td>0.0001</td></tr><tr><td>Tricuspid</td><td>155 (6)</td><td>57 (5)</td><td>98 (6)</td><td>0.61</td></tr><tr><td>Pulmonary</td><td>36 (2)</td><td>16 (2)</td><td>20 (1)</td><td>0.49</td></tr><tr><td>Coronary artery bypass graft surgery</td><td>1241 (49)</td><td>398 (40)</td><td>843 (54)</td><td>0.001</td></tr><tr><td>Combined surgery</td><td>780 (31)</td><td>279 (28)</td><td>501 (32)</td><td>0.02</td></tr><tr><td>Ascending aorta</td><td>286 (11)</td><td>121 (12)</td><td>165 (11)</td><td>0.24</td></tr><tr><td>Aortic arch</td><td>40 (2)</td><td>12 (1)</td><td>28 (2)</td><td>0.25</td></tr><tr><td>Aortic dissection</td><td>40 (2)</td><td>15 (2)</td><td>25 (2)</td><td>0.87</td></tr><tr><td>Others (atrial fibrillation ablation, left atrial appendage occlusion, interventricular communication, myxoma...)</td><td>227 (9)</td><td>71 (7)</td><td>156 (10)</td><td>0.01</td></tr></tbody></table>

we demonstrated an association with preoperative (right and left) cardiac function parameters, NE may also be used as a treatment for low cardiac output syndrome [18]. Fourth, we identified factors that are associated with the vasoplegic syndrome [19,20]. Some of these factors (fibrinogen transfusion, beta-blocker maintenance, GIK) may be surprising because they are the opposite of what would be expected. Previous studies have demonstrated that these factors are associated with vasomotor tone alteration and arterial

hypotension [21]. Fibrinogen has several effects on microcirculation that can be more pronounced in the case of an inflammatory process [22]. Thus, fibrinogen can alter vasomotor tone. Of these factors, some factors may be modifiable, so therapeutic options can be discussed such as the treatment for anemia (patient blood management), the withdrawal of beta-blocker therapy on the morning of the surgery, the choice of cardioplegia, and the use of normothermia. Taking together these factors illustrate the high
<table><caption>**Table 1**
Demographic, medical history and treatment according to norepinephrine use.</caption><thead><tr><th></th><th>Overall population N = 2541</th><th>Norepinephrine free N = 992</th><th>Norepinephrine N = 1549</th><th>p-value</th></tr></thead><tbody><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td></tr><tr><td>Age (years)</td><td>69 [61,74]</td><td>67 [59,73]</td><td>69 [63,75]</td><td>0.0001</td></tr><tr><td>Gender (male)</td><td>1928 (76)</td><td>749 (76)</td><td>1179 (76)</td><td>0.73</td></tr><tr><td>Body Mass Index (kg.m<sup>-2</sup>)</td><td>27.9 [24.4,30.5]</td><td>26.8 [24,30.1]</td><td>26.8 [24,30.6]</td><td>0.02</td></tr><tr><td>Chronic high blood pressure</td><td>1664 (66)</td><td>634 (64)</td><td>1030 (67)</td><td>0.1</td></tr><tr><td>Coronary disease</td><td>1205 (48)</td><td>387 (39)</td><td>818 (52)</td><td>0.0001</td></tr><tr><td>Atrial fibrillation</td><td>439 (17)</td><td>127 (13)</td><td>312 (20)</td><td>0.0001</td></tr><tr><td>Peripheral arterial disease</td><td>240 (10)</td><td>83 (8)</td><td>157 (10)</td><td>0.14</td></tr><tr><td>Carotid artery stenosis</td><td>136 (5)</td><td>45 (5)</td><td>91 (6)</td><td>0.14</td></tr><tr><td>Stroke</td><td>204 (8)</td><td>58 (6)</td><td>146 (9)</td><td>0.001</td></tr><tr><td>Insulin-dependent diabetes</td><td>179 (7)</td><td>67 (7)</td><td>112 (6)</td><td>0.69</td></tr><tr><td>Non insulin-dependent diabetes</td><td>521 (21)</td><td>198 (20)</td><td>323 (21)</td><td>0.61</td></tr><tr><td>Dyslipidemia</td><td>1134 (45)</td><td>388 (39)</td><td>746 (48)</td><td>0.0001</td></tr><tr><td>Chronic renal failure (eGFR &lt;60 (mL.min<sup>-1</sup>.m<sup>-2</sup>)</td><td>415 (16)</td><td>117 (12)</td><td>298 (19)</td><td>0.0001</td></tr><tr><td>Dialysis</td><td>20 (1)</td><td>2 (0.2)</td><td>18 (1)</td><td>0.01</td></tr><tr><td>Estimated glomerular filtration rate (ml.min<sup>-1</sup>.m<sup>-2</sup>)</td><td>81 [66,97]</td><td>83 [70,99]</td><td>80 [64,96]</td><td>0.001</td></tr><tr><td>Haematocrit (%)</td><td>41.4 [38.3, 44.3]</td><td>42 [39,45.6]</td><td>41 [37.6,44]</td><td>0.001</td></tr><tr><td>Left ventricular ejection fraction (%)</td><td>59 [10]</td><td>60 [10]</td><td>56 [11]</td><td>0.0001</td></tr><tr><td>Right ventricular dysfunction</td><td>95 (4)</td><td>20 (2)</td><td>75 (5)</td><td>0.0001</td></tr><tr><td>Pulmonary artery pressure (mmHg)</td><td>28 [24,32]</td><td>28 [25,35]</td><td>30 [23,40]</td><td>0.0001</td></tr><tr><td>Medications</td><td></td><td></td><td></td><td></td></tr><tr><td>Beta-blockers</td><td>954 (38)</td><td>375 (38)</td><td>579 (37)</td><td>0.0001</td></tr><tr><td>Withdraw on the morning of surgery</td><td>533 (21)</td><td>132 (13)</td><td>401 (26)</td><td></td></tr><tr><td>Calcium channel blockers</td><td>533 (21)</td><td>205 (20)</td><td>328 (21)</td><td>0.76</td></tr><tr><td>Angiotensin-converting enzyme inhibitor</td><td>548 (15)</td><td>182 (16)</td><td>366 (13)</td><td>0.001</td></tr><tr><td>Withdraw 24 h before surgery</td><td>354 (65)</td><td>160 (87)</td><td>194 (53)</td><td></td></tr><tr><td>Amiodarone</td><td>141 (6)</td><td>44 (4)</td><td>97 (6)</td><td>0.05</td></tr><tr><td>Anti-aldosterone</td><td>98 (4)</td><td>27 (3)</td><td>71 (5)</td><td>0.02</td></tr><tr><td>Aspirin</td><td>1333 (53)</td><td>472 (48)</td><td>861 (56)</td><td>0.0001</td></tr><tr><td>Clopidogrel</td><td>207 (8)</td><td>75 (8)</td><td>132 (9)</td><td>0.41</td></tr><tr><td>Vitamin K antagonist</td><td>140 (6)</td><td>38 (4)</td><td>102 (7)</td><td>0.003</td></tr><tr><td>Statin</td><td>1383 (55)</td><td>485 (49)</td><td>898 (58)</td><td>0.0001</td></tr><tr><td>Loop diuretic</td><td>558 (22)</td><td>157 (16)</td><td>401 (26)</td><td>0.001</td></tr><tr><td>Insulin</td><td>179 (7)</td><td>67 (6)</td><td>112 (7)</td><td>0.69</td></tr><tr><td>Metformin</td><td>241 (9)</td><td>92 (9)</td><td>149 (10)</td><td>0.83</td></tr><tr><td>Other antidiabetic drugs</td><td>242 (9)</td><td>93 (9)</td><td>149 (10)</td><td>0.89</td></tr><tr><td>Scores</td><td></td><td></td><td></td><td></td></tr><tr><td>Euroscore 2</td><td>1.8 [1, 3.5]</td><td>1.4 [0.8,2.5]</td><td>2.1 [1.1,4.1]</td><td>0.0001</td></tr><tr><td>American Society Anesthesiology score (ASA)</td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>9 (2)</td><td>7 (1)</td><td>2 (1)</td><td></td></tr><tr><td>2</td><td>235 (10)</td><td>116 (12)</td><td>119 (7)</td><td></td></tr><tr><td>3</td><td>1985 (79)</td><td>793 (79)</td><td>1192 (76)</td><td>0.0001</td></tr><tr><td>4</td><td>297 (12)</td><td>71 (7)</td><td>226 (15)</td><td></td></tr><tr><td>5</td><td>15 (1)</td><td>5 (1)</td><td>10 (1)</td><td></td></tr><tr><td>Type of surgery</td><td></td><td></td><td></td><td></td></tr><tr><td>Urgent</td><td>347 (14)</td><td>77 (8)</td><td>270 (17)</td><td>0.0001</td></tr><tr><td>Preoperative sepsis</td><td>69 (3)</td><td>11 (1)</td><td>58 (4)</td><td>0.0001</td></tr><tr><td>Previous cardiac surgery</td><td>97 (4)</td><td>21 (2)</td><td>76 (5)</td><td>0.0001</td></tr><tr><td>Active endocarditis</td><td>65 (3)</td><td>8 (1)</td><td>57 (4)</td><td>0.0001</td></tr><tr><td>Valvular surgery</td><td>1453 (57)</td><td>629 (63)</td><td>824 (53)</td><td>0.0001</td></tr><tr><td>Mitral</td><td>435 (17)</td><td>142 (14)</td><td>293 (19)</td><td>0.003</td></tr><tr><td>Aortic</td><td>1065 (42)</td><td>503 (51)</td><td>562 (36)</td><td>0.0001</td></tr><tr><td>Tricuspid</td><td>155 (6)</td><td>57 (5)</td><td>98 (6)</td><td>0.61</td></tr><tr><td>Pulmonary</td><td>36 (2)</td><td>16 (2)</td><td>20 (1)</td><td>0.49</td></tr><tr><td>Coronary artery bypass graft surgery</td><td>1241 (49)</td><td>398 (40)</td><td>843 (54)</td><td>0.001</td></tr><tr><td>Combined surgery</td><td>780 (31)</td><td>279 (28)</td><td>501 (32)</td><td>0.02</td></tr><tr><td>Ascending aorta</td><td>286 (11)</td><td>121 (12)</td><td>165 (11)</td><td>0.24</td></tr><tr><td>Aortic arch</td><td>40 (2)</td><td>12 (1)</td><td>28 (2)</td><td>0.25</td></tr><tr><td>Aortic dissection</td><td>40 (2)</td><td>15 (2)</td><td>25 (2)</td><td>0.87</td></tr><tr><td>Others (atrial fibrillation ablation, left atrial appendage occlusion, interventricular communication, myxoma...)</td><td>227 (9)</td><td>71 (7)</td><td>156 (10)</td><td>0.01</td></tr></tbody></table>

we demonstrated an association with preoperative (right and left) cardiac function parameters, NE may also be used as a treatment for low cardiac output syndrome [18]. Fourth, we identified factors that are associated with the vasoplegic syndrome [19,20]. Some of these factors (fibrinogen transfusion, beta-blocker maintenance, GIK) may be surprising because they are the opposite of what would be expected. Previous studies have demonstrated that these factors are associated with vasomotor tone alteration and arterial

hypotension [21]. Fibrinogen has several effects on microcirculation that can be more pronounced in the case of an inflammatory process [22]. Thus, fibrinogen can alter vasomotor tone. Of these factors, some factors may be modifiable, so therapeutic options can be discussed such as the treatment for anemia (patient blood management), the withdrawal of beta-blocker therapy on the morning of the surgery, the choice of cardioplegia, and the use of normothermia. Taking together these factors illustrate the high
<table><caption>**Table 2**
Vaso-active support during surgery and ICU course.</caption><thead><tr><th></th><th>Overall population N = 2541</th><th>Norepinephrine free N = 992</th><th>Norepinephrine N = 1549</th><th>p-value</th></tr></thead><tbody><tr><td><strong>Operating room</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Ephedrine</td><td>1405 (55)</td><td>466 (60.4)</td><td>446 (57.8)</td><td>0.31</td></tr><tr><td>Ephedrine total dose (mg)</td><td>15 [9,27]</td><td>12 [9,21]</td><td>18 [12,30]</td><td>0.88</td></tr><tr><td>Phenylephrine</td><td>604 (24)</td><td>215 (22)</td><td>389 (25)</td><td>0.05</td></tr><tr><td>Total dose (mg)</td><td>0.2 [0.1,0.4]</td><td>0.2 [0.1,0.3]</td><td>0.2 [0.1,0.4]</td><td>0.47</td></tr><tr><td>Norepinephrine</td><td>1227 (48)</td><td>0</td><td>1277 (82)</td><td>&lt;0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.17 [0.1, 0.28]</td><td></td><td>0.17 [0.11,0.28]</td><td>0.10</td></tr><tr><td>Dobutamine</td><td>256 (10)</td><td>45 (5)</td><td>211 (14)</td><td>0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>7 [5,10]</td><td>5 [4,10]</td><td>7 [5,10]</td><td>0.98</td></tr><tr><td>Epinephrine</td><td>14 (1)</td><td>1 (0.2)</td><td>13 (1)</td><td>0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.43 [0.18,0.64]</td><td>0.4 [0.4,0.4]</td><td>0.4 [0.16,0.67]</td><td>NA</td></tr><tr><td><strong>Intensive care unit</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Norepinephrine</td><td></td><td></td><td></td><td></td></tr><tr><td>Norepinephrine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.11 [0.06,0.20]</td><td>0</td><td>0.11 [0.06,0.20]</td><td>0.0001</td></tr><tr><td>Norepinephrine infusion time (hours)</td><td>10 [3,24]</td><td>0</td><td>10 [3,24]</td><td>0.0001</td></tr><tr><td>Dobutamine</td><td>315 (12)</td><td>48 (5)</td><td>265 (17)</td><td>0.0001</td></tr><tr><td>Dobutamine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>7 [5,9]</td><td>5 [4,5]</td><td>7.5 [5,10]</td><td>0.0001</td></tr><tr><td>Dobutamine infusion time (hours)</td><td>30 [17,60]</td><td>15 [5,34]</td><td>35 [19,362]</td><td>0.0001</td></tr><tr><td>Epinephrine</td><td>28 (1)</td><td></td><td>28 (2)</td><td>0.002</td></tr><tr><td>Epinephrine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.26 [0.08,0.92]</td><td>0</td><td>0.26 [0.08,0.92]</td><td>0.0001</td></tr><tr><td>Epinephrine infusion time (hours)</td><td>20 [6,40]</td><td>0</td><td>20 [6,40]</td><td>0.0001</td></tr></tbody></table>

severity of illness which is associated with chronic vasomotor tone and/or heart alterations [23,24].

Patients treated with NE have a high incidence of postoperative complications, particularly renal complications and death. We observed a higher rate of complications for reasons that are: (i)

patients with a high number of risk factors are those who probably have higher severity illness, thus higher risk for postoperative complications, (ii) NE may also be the translation of an underlying abnormal process, (iii) NE may alter tissue perfusion. Literature on this subject is sparse and contradictory [25-27]. The VANCS study

<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Forest plot of factors associated with norepinephrine use.</figcaption></figure>
<table><caption>**Table 2**
Vaso-active support during surgery and ICU course.</caption><thead><tr><th></th><th>Overall population N = 2541</th><th>Norepinephrine free N = 992</th><th>Norepinephrine N = 1549</th><th>p-value</th></tr></thead><tbody><tr><td><strong>Operating room</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Ephedrine</td><td>1405 (55)</td><td>466 (60.4)</td><td>446 (57.8)</td><td>0.31</td></tr><tr><td>Ephedrine total dose (mg)</td><td>15 [9,27]</td><td>12 [9,21]</td><td>18 [12,30]</td><td>0.88</td></tr><tr><td>Phenylephrine</td><td>604 (24)</td><td>215 (22)</td><td>389 (25)</td><td>0.05</td></tr><tr><td>Total dose (mg)</td><td>0.2 [0.1,0.4]</td><td>0.2 [0.1,0.3]</td><td>0.2 [0.1,0.4]</td><td>0.47</td></tr><tr><td>Norepinephrine</td><td>1227 (48)</td><td>0</td><td>1277 (82)</td><td>&lt;0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.17 [0.1, 0.28]</td><td></td><td>0.17 [0.11,0.28]</td><td>0.10</td></tr><tr><td>Dobutamine</td><td>256 (10)</td><td>45 (5)</td><td>211 (14)</td><td>0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>7 [5,10]</td><td>5 [4,10]</td><td>7 [5,10]</td><td>0.98</td></tr><tr><td>Epinephrine</td><td>14 (1)</td><td>1 (0.2)</td><td>13 (1)</td><td>0.0001</td></tr><tr><td>Median maximal dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.43 [0.18,0.64]</td><td>0.4 [0.4,0.4]</td><td>0.4 [0.16,0.67]</td><td>NA</td></tr><tr><td><strong>Intensive care unit</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Norepinephrine</td><td></td><td></td><td></td><td></td></tr><tr><td>Norepinephrine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.11 [0.06,0.20]</td><td>0</td><td>0.11 [0.06,0.20]</td><td>0.0001</td></tr><tr><td>Norepinephrine infusion time (hours)</td><td>10 [3,24]</td><td>0</td><td>10 [3,24]</td><td>0.0001</td></tr><tr><td>Dobutamine</td><td>315 (12)</td><td>48 (5)</td><td>265 (17)</td><td>0.0001</td></tr><tr><td>Dobutamine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>7 [5,9]</td><td>5 [4,5]</td><td>7.5 [5,10]</td><td>0.0001</td></tr><tr><td>Dobutamine infusion time (hours)</td><td>30 [17,60]</td><td>15 [5,34]</td><td>35 [19,362]</td><td>0.0001</td></tr><tr><td>Epinephrine</td><td>28 (1)</td><td></td><td>28 (2)</td><td>0.002</td></tr><tr><td>Epinephrine maximal infusion dose (µg.kg<sup>-1</sup>.min<sup>-1</sup>)</td><td>0.26 [0.08,0.92]</td><td>0</td><td>0.26 [0.08,0.92]</td><td>0.0001</td></tr><tr><td>Epinephrine infusion time (hours)</td><td>20 [6,40]</td><td>0</td><td>20 [6,40]</td><td>0.0001</td></tr></tbody></table>

severity of illness which is associated with chronic vasomotor tone and/or heart alterations [23,24].

Patients treated with NE have a high incidence of postoperative complications, particularly renal complications and death. We observed a higher rate of complications for reasons that are: (i)

patients with a high number of risk factors are those who probably have higher severity illness, thus higher risk for postoperative complications, (ii) NE may also be the translation of an underlying abnormal process, (iii) NE may alter tissue perfusion. Literature on this subject is sparse and contradictory [25-27]. The VANCS study

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Forest plot of factors associated with norepinephrine use.</figcaption></figure>
<table><caption>**Table 3**
Postoperative course according to norepinephrine use, after propensity matching.</caption><thead><tr><th></th><th>Norepinephrine free N = 658</th><th>Norepinephrine N = 658</th><th>p-value</th></tr></thead><tbody><tr><td>Primary endpoint</td><td></td><td></td><td></td></tr><tr><td>Major adverse kidney and cerebral events</td><td>77 (12)</td><td>144 (22)</td><td>0.0001</td></tr><tr><td>Secondary endpoints</td><td></td><td></td><td></td></tr><tr><td>Neurologic</td><td></td><td></td><td></td></tr><tr><td>Stroke</td><td>12 (2)</td><td>51 (8)</td><td>0.09</td></tr><tr><td>Cardiac</td><td></td><td></td><td></td></tr><tr><td>New episode of atrial fibrillation</td><td>164 (25)</td><td>153 (23)</td><td></td></tr><tr><td>Ventricular tachycardia or ventricular fibrillation</td><td>31 (5)</td><td>29 (4)</td><td>0.39</td></tr><tr><td>Myocardial infarction</td><td>5 (1)</td><td>9 (2)</td><td></td></tr><tr><td>Acute kidney injury</td><td>65 (10)</td><td>126 (19)</td><td>0.0001</td></tr><tr><td>Renal replacement therapy</td><td>4 (1)</td><td>12 (2)</td><td></td></tr><tr><td>Death</td><td>3 (0.5)</td><td>16 (3)</td><td>0.005</td></tr><tr><td>ICU length of stays (days)</td><td>2 [2-3]</td><td>3 [2-5]</td><td>0.001</td></tr><tr><td>Hospital length of stays (days)</td><td>9 [7-11]</td><td>9 [7-12]</td><td>0.02</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**Fig. 3.** Postoperative complications according to norepinephrine use in the propensity score-matched cohort. Major adverse kidney and cerebral events include stroke, acute kidney injury, and death.</figcaption></figure>

demonstrated that NE may be associated with a higher incidence of AKI than vasopressin [9]. A randomized controlled trial demonstrated a lower complication rate with NE than with dopamine [28]. In absence of a randomized study evaluating NE against a placebo or in the context of blood pressure optimization, we cannot conclude a causal effect between NE exposure and postoperative outcomes. Our results provide data that can help the physician to design further studies focusing on vasopressor therapy, management of vasopressor [29], vasopressor sparing strategies [30], and their impact on outcomes (NCT05568160)

[31]. Because we have identified several risk factors for NE use, physicians are able to select a population at high risk of postoperative complications for whom perioperative bundle care may be clinically relevant to improve peri-operative course [32,33].

The present study has limitations. This is an observational study that included a fraction of the overall surgical patients admitted during the study period, thus the study may have omitted some potential factors. We have also excluded intra-operative hemorrhagic shock and incomplete data. We observed a lower rate of
<table><caption>**Table 3**
Postoperative course according to norepinephrine use, after propensity matching.</caption><thead><tr><th></th><th>Norepinephrine free N = 658</th><th>Norepinephrine N = 658</th><th>p-value</th></tr></thead><tbody><tr><td>Primary endpoint</td><td></td><td></td><td></td></tr><tr><td>Major adverse kidney and cerebral events</td><td>77 (12)</td><td>144 (22)</td><td>0.0001</td></tr><tr><td>Secondary endpoints</td><td></td><td></td><td></td></tr><tr><td>Neurologic</td><td></td><td></td><td></td></tr><tr><td>Stroke</td><td>12 (2)</td><td>51 (8)</td><td>0.09</td></tr><tr><td>Cardiac</td><td></td><td></td><td></td></tr><tr><td>New episode of atrial fibrillation</td><td>164 (25)</td><td>153 (23)</td><td></td></tr><tr><td>Ventricular tachycardia or ventricular fibrillation</td><td>31 (5)</td><td>29 (4)</td><td>0.39</td></tr><tr><td>Myocardial infarction</td><td>5 (1)</td><td>9 (2)</td><td></td></tr><tr><td>Acute kidney injury</td><td>65 (10)</td><td>126 (19)</td><td>0.0001</td></tr><tr><td>Renal replacement therapy</td><td>4 (1)</td><td>12 (2)</td><td></td></tr><tr><td>Death</td><td>3 (0.5)</td><td>16 (3)</td><td>0.005</td></tr><tr><td>ICU length of stays (days)</td><td>2 [2-3]</td><td>3 [2-5]</td><td>0.001</td></tr><tr><td>Hospital length of stays (days)</td><td>9 [7-11]</td><td>9 [7-12]</td><td>0.02</td></tr></tbody></table>

<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Postoperative complications according to norepinephrine use in the propensity score-matched cohort. Major adverse kidney and cerebral events include stroke, acute kidney injury, and death.</figcaption></figure>

demonstrated that NE may be associated with a higher incidence of AKI than vasopressin [9]. A randomized controlled trial demonstrated a lower complication rate with NE than with dopamine [28]. In absence of a randomized study evaluating NE against a placebo or in the context of blood pressure optimization, we cannot conclude a causal effect between NE exposure and postoperative outcomes. Our results provide data that can help the physician to design further studies focusing on vasopressor therapy, management of vasopressor [29], vasopressor sparing strategies [30], and their impact on outcomes (NCT05568160)

[31]. Because we have identified several risk factors for NE use, physicians are able to select a population at high risk of postoperative complications for whom perioperative bundle care may be clinically relevant to improve peri-operative course [32,33].

The present study has limitations. This is an observational study that included a fraction of the overall surgical patients admitted during the study period, thus the study may have omitted some potential factors. We have also excluded intra-operative hemorrhagic shock and incomplete data. We observed a lower rate of
intra-operative transfusion (red blood cell or fibrinogen) than what would be expected, and we cannot exclude some bias. Risk factors were evaluated by using a multiple logistic regression model that demonstrated only association and not causation. Because of the study design, we cannot demonstrate a causal relation effect between NE and complications. The quality of the model was good, and the predictability was moderate. Further study may externally validate our results.

## Conclusions

The prevalence of NE use is high for cardiac surgical patients, often used for short periods with low doses. Many preoperative and surgical factors are associated with its use. Patients treated with NE have a higher incidence of major postoperative complications.

## Declarations

### Ethical approval and consent to participate

This study was approved by the Institutional Review Board (CPP 2017-A01324-49) for human subjects/Independent Ethics Committee. All patients have received a written document for research purposes. The study design adheres to the requirements of the Medical Research Involving Human Subject Act and of the Declaration of Helsinki.

## Author contributions

PGG designed the study, performed data analysis, and drafted the manuscript. VC, BD, VB, OAA, OB, KM, MPM, BB, MN, PGG made contribution to study conception, and data analysis. BD, VC, MPM, OAA substantially contributed to data collection. All the authors approved the final version of the paper.

## Funding

None to declare.

## Ethical statement

We performed a multicenter observational prospective study that was approved by the French ethical committee (Comité De Protection Des Personnes Sud Mediterranee I, 2017-A01324-49, Chairman: Pr Y. JAMMES) for human subjects. The study was conducted in the anesthesia and critical care cardiac surgical department of the university-affiliated tertiary hospitals of Dijon, Amiens, Rouen and Strasbourg, France, from 2017 to 2021. All patients have received a written document for research purposes, and gave their consent prior to participate. The study design adheres to the requirements of the Medical Research Involving Human Subject Act and of Declaration of Helsinki. The study complied with STROBE guidelines

## Conflict of interest

None.

## Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

## Acknowledgements

None.

## Appendix. Collaborator study group

<table><thead><tr><th>Name</th><th>Full affiliation</th></tr></thead><tbody><tr><td>Audrey Martin</td><td rowspan="2">Department of Anaesthesiology and Critical Care Medicine, Dijon University Medical Centre, 21000 Dijon, France</td></tr><tr><td>Valerian Duclos</td></tr><tr><td>Alexandra Spitz</td><td></td></tr><tr><td>Tiberiu Constandache</td><td></td></tr><tr><td>Sandrine Grosjean</td><td></td></tr><tr><td>Mohamed Radhouani</td><td></td></tr><tr><td>Jean-Baptiste Anciaux</td><td></td></tr><tr><td>Anis Missaoui</td><td></td></tr><tr><td>Marie-Catherine Morgant</td><td rowspan="4">Department of Anaesthesiology and Critical Care Medicine, Rouen University Medical Centre, 76000 Rouen, France</td></tr><tr><td>Olivier Bouchot</td></tr><tr><td>Saed Jazayeri</td></tr><tr><td>Zoe Demailly</td></tr><tr><td>Pierre Huette</td><td rowspan="4">Department of Anaesthesiology and Critical Care Medicine, Strasbourg University Medical Centre, Strasbourg, France</td></tr><tr><td>Mathieu Guilbart</td></tr><tr><td>Patricia Besserve</td></tr><tr><td>Christophe Beyls</td></tr><tr><td>Hervé Dupont</td><td rowspan="2">Department of Cardiovascular Surgery, University Hospitals of Strasbourg, Strasbourg, France</td></tr><tr><td>Michel Kindo</td></tr><tr><td>Thibaut Wipf</td><td>Department of Cardiac Surgery, Dijon University Medical Centre, 21000 Dijon, France</td></tr></tbody></table>

## Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.accpm.2023.101200.

## References

[1] Lomivorotov VV, Efremov SM, Kirov MY, Fominskiy EV, Karaskov AM. Low-cardiac-output syndrome after cardiac surgery. J Cardiothorac Vasc Anesth 2017;31:291-308. http://dx.doi.org/10.1053/j.jvca.2016.05.029.

[2] Ortoleva J, Shapeton A, Vanneman M, Dalia AA. Vasoplegia during cardiopulmonary bypass: current literature and rescue therapy options. J Cardiothorac Vasc Anesth 2019. http://dx.doi.org/10.1053/j.jvca.2019.12.013.

[3] Levin MA, Lin H-M, Castillo JG, Adams DH, Reich DL, Fischer GW. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation 2009;120:1664-71. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.814533.

[4] Kerbaul F, Collart F, Giorgi R, Ibrahim Z, Guillen J-C, Gil J-M, et al. Role of endogenous adenosine as a predictive marker of vasoplegia during cardiopulmonary bypass and postoperative severe systemic inflammatory response. Crit Care Med 2006;34:640-5. http://dx.doi.org/10.1097/01.CCM.0000201005.34203.50.

[5] Mekontso-Dessap A, Houël R, Soustelle C, Kirsch M, Thébert D, Loisance DY. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428-32. http://dx.doi.org/10.1016/s0003-4975(01)02486-9.

[6] Guarracino F, Habicher M, Treskatsch S, Sander M, Szekely A, Paternoster G, et al. Vasopressor therapy in cardiac surgery-an experts' consensus statement. J Cardiothorac Vasc Anesth 2021;35:1018-29. http://dx.doi.org/10.1053/j.jvca.2020.11.032.

[7] Evora PRB, Alves Junior L, Ferreira CA, Menardi AC, Bassetto S, Rodrigues AJ, et al. Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised. Rev Bras Cir Cardiovasc Orgao Of Soc Bras Cir Cardiovasc 2015;30:84-92. http://dx.doi.org/10.5935/1678-9741.20140115.

[8] Dünser MW, Bouvet O, Knotzer H, Arulkumaran N, Hajjar LA, Ulmer H, et al. Vasopressin in cardiac surgery: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2018;32:2225-32. http://dx.doi.org/10.1053/j.jvca.2018.04.006.
intra-operative transfusion (red blood cell or fibrinogen) than what would be expected, and we cannot exclude some bias. Risk factors were evaluated by using a multiple logistic regression model that demonstrated only association and not causation. Because of the study design, we cannot demonstrate a causal relation effect between NE and complications. The quality of the model was good, and the predictability was moderate. Further study may externally validate our results.

## Conclusions

The prevalence of NE use is high for cardiac surgical patients, often used for short periods with low doses. Many preoperative and surgical factors are associated with its use. Patients treated with NE have a higher incidence of major postoperative complications.

## Declarations

### Ethical approval and consent to participate

This study was approved by the Institutional Review Board (CPP 2017-A01324-49) for human subjects/Independent Ethics Committee. All patients have received a written document for research purposes. The study design adheres to the requirements of the Medical Research Involving Human Subject Act and of the Declaration of Helsinki.

## Author contributions

PGG designed the study, performed data analysis, and drafted the manuscript. VC, BD, VB, OAA, OB, KM, MPM, BB, MN, PGG made contribution to study conception, and data analysis. BD, VC, MPM, OAA substantially contributed to data collection. All the authors approved the final version of the paper.

## Funding

None to declare.

## Ethical statement

We performed a multicenter observational prospective study that was approved by the French ethical committee (Comité De Protection Des Personnes Sud Mediterranee I, 2017-A01324-49, Chairman: Pr Y. JAMMES) for human subjects. The study was conducted in the anesthesia and critical care cardiac surgical department of the university-affiliated tertiary hospitals of Dijon, Amiens, Rouen and Strasbourg, France, from 2017 to 2021. All patients have received a written document for research purposes, and gave their consent prior to participate. The study design adheres to the requirements of the Medical Research Involving Human Subject Act and of Declaration of Helsinki. The study complied with STROBE guidelines

## Conflict of interest

None.

## Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

## Acknowledgements

None.

## Appendix. Collaborator study group

<table><thead><tr><th>Name</th><th>Full affiliation</th></tr></thead><tbody><tr><td>Audrey Martin</td><td rowspan="2">Department of Anaesthesiology and Critical Care Medicine, Dijon University Medical Centre, 21000 Dijon, France</td></tr><tr><td>Valerian Duclos</td></tr><tr><td>Alexandra Spitz</td><td></td></tr><tr><td>Tiberiu Constandache</td><td></td></tr><tr><td>Sandrine Grosjean</td><td></td></tr><tr><td>Mohamed Radhouani</td><td></td></tr><tr><td>Jean-Baptiste Anciaux</td><td></td></tr><tr><td>Anis Missaoui</td><td></td></tr><tr><td>Marie-Catherine Morgant</td><td rowspan="4">Department of Anaesthesiology and Critical Care Medicine, Rouen University Medical Centre, 76000 Rouen, France</td></tr><tr><td>Olivier Bouchot</td></tr><tr><td>Saed Jazayeri</td></tr><tr><td>Zoe Demailly</td></tr><tr><td>Pierre Huette</td><td rowspan="4">Department of Anaesthesiology and Critical Care Medicine, Strasbourg University Medical Centre, Strasbourg, France</td></tr><tr><td>Mathieu Guilbart</td></tr><tr><td>Patricia Besserve</td></tr><tr><td>Christophe Beyls</td></tr><tr><td>Hervé Dupont</td><td rowspan="2">Department of Cardiovascular Surgery, University Hospitals of Strasbourg, Strasbourg, France</td></tr><tr><td>Michel Kindo</td></tr><tr><td>Thibaut Wipf</td><td>Department of Cardiac Surgery, Dijon University Medical Centre, 21000 Dijon, France</td></tr></tbody></table>

## Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.accpm.2023.101200.

## References

[1] Lomivorotov VV, Efremov SM, Kirov MY, Fominskiy EV, Karaskov AM. Low-cardiac-output syndrome after cardiac surgery. J Cardiothorac Vasc Anesth 2017;31:291-308. http://dx.doi.org/10.1053/j.jvca.2016.05.029.

[2] Ortoleva J, Shapeton A, Vanneman M, Dalia AA. Vasoplegia during cardiopulmonary bypass: current literature and rescue therapy options. J Cardiothorac Vasc Anesth 2019. http://dx.doi.org/10.1053/j.jvca.2019.12.013.

[3] Levin MA, Lin H-M, Castillo JG, Adams DH, Reich DL, Fischer GW. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation 2009;120:1664-71. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.814533.

[4] Kerbaul F, Collart F, Giorgi R, Ibrahim Z, Guillen J-C, Gil J-M, et al. Role of endogenous adenosine as a predictive marker of vasoplegia during cardiopulmonary bypass and postoperative severe systemic inflammatory response. Crit Care Med 2006;34:640-5. http://dx.doi.org/10.1097/01.CCM.0000201005.34203.50.

[5] Mekontso-Dessap A, Houël R, Soustelle C, Kirsch M, Thébert D, Loisance DY. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428-32. http://dx.doi.org/10.1016/s0003-4975(01)02486-9.

[6] Guarracino F, Habicher M, Treskatsch S, Sander M, Szekely A, Paternoster G, et al. Vasopressor therapy in cardiac surgery-an experts' consensus statement. J Cardiothorac Vasc Anesth 2021;35:1018-29. http://dx.doi.org/10.1053/j.jvca.2020.11.032.

[7] Evora PRB, Alves Junior L, Ferreira CA, Menardi AC, Bassetto S, Rodrigues AJ, et al. Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised. Rev Bras Cir Cardiovasc Orgao Of Soc Bras Cir Cardiovasc 2015;30:84-92. http://dx.doi.org/10.5935/1678-9741.20140115.

[8] Dünser MW, Bouvet O, Knotzer H, Arulkumaran N, Hajjar LA, Ulmer H, et al. Vasopressin in cardiac surgery: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2018;32:2225-32. http://dx.doi.org/10.1053/j.jvca.2018.04.006.
[9] Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA, et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology 2017;126:85-93. http://dx.doi.org/10.1097/ALN.00000000000001434.

[10] Toulouse E, Granier S, Nicolas-Robin A, Bahans C, Milman A, Andrieu VR, et al. The French clinical research in the European Community regulation era. Anaesth Crit Care Pain Med 2022;42101192. http://dx.doi.org/10.1016/j.accpm.2022.101192.

[11] Doussau A, Perez P, Puntous M, Calderon J, Jeanne M, Germain C, et al. Fresh-frozen plasma transfusion did not reduce 30-day mortality in patients undergoing cardiopulmonary bypass cardiac surgery with excessive bleeding: the PLASMACARD multicenter cohort study. Transfusion (Paris) 2014;54:1114-24. http://dx.doi.org/10.1111/trf.12422.

[12] Abou-Arab O, Huette P, Martineau L, Beauvalot C, Beyls C, Josse E, et al. Hyperoxia during cardiopulmonary bypass does not decrease cardiovascular complications following cardiac surgery: the CARDIOX randomized clinical trial. Intensive Care Med 2019;45:1413-21. http://dx.doi.org/10.1007/s00134-019-05761-4.

[13] Guinot P-G, Ellouze O, Grosjean S, Berthoud V, Constandache T, Radhouani M, et al. Anaesthesia and ICU sedation with sevoflurane do not reduce myocardial injury in patients undergoing cardiac surgery: a randomized prospective study. Medicine (Baltimore) 2020;99e23253. http://dx.doi.org/10.1097/MD.000000000000023253.

[14] Jammer I, Wickboldt N, Sander M, Smith A, Schultz MJ, Pelosi P, et al. Standards for definitions and use of outcome measures for clinical effectiveness research in perioperative medicine: European perioperative clinical outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on perioperative outcome measures. Eur J Anaesthesiol 2015;32:88-105. http://dx.doi.org/10.1097/EJA.00000000000000118.

[15] Schulte PJ, Mascha EJ. Propensity score methods: theory and practice for anesthesia research. Anesth Analg 2018;127:1074-84. http://dx.doi.org/10.1213/ANE.00000000000002920.

[16] Vail EA, Shieh M-S, Pekow PS, Gershengorn HB, Walkey AJ, Lindenauer PK, et al. Use of vasoactive medications after cardiac surgery in the United States. Ann Am Thorac Soc 2021;18:103-11. http://dx.doi.org/10.1513/Annual-ATS.202005-4650C.

[17] García PS, Brown CHIV. Phenylephrine or ephedrine for intraoperative hypotension? Consider the cerebral microcirculation. Anesthesiology 2021;135:775-7. http://dx.doi.org/10.1097/ALN.00000000000003975.

[18] Gao F, Zhang Y. Inotrope use and intensive care unit mortality in patients with cardiogenic shock: an analysis of a large electronic intensive care unit database. Front Cardiovasc Med 2021;8696138. http://dx.doi.org/10.3389/fcvm.2021.696138.

[19] Bastopcu M, Sargin M, Kuplay H, Erdoğan SB, Yapıcı N, Aka SA. Risk factors for vasoplegia after coronary artery bypass and valve surgery. J Card Surg 2021;36:2729-34. http://dx.doi.org/10.1111/jocs.15663.

[20] Dayan V, Cal R, Giangrossi F. Risk factors for vasoplegia after cardiac surgery: a meta-analysis. Interact Cardiovasc Thorac Surg 2019;28:838-44. http://dx.doi.org/10.1093/icvts/ivy352.

[21] POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet Lond Engl 2008;371:1839-47. http://dx.doi.org/10.1016/S0140-6736(08)60601-7.

[22] Lominadze D, Dean WL, Tyagi SC, Roberts AM. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease. Acta Physiol Oxf Engl 2010;198:1-13. http://dx.doi.org/10.1111/j.1748-1716.2009.02037.x.

[23] Harrison DG, Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: implications for impaired vasomotion. Am J Cardiol 1995;75:75B-81B. http://dx.doi.org/10.1016/0002-9149(95)80018-n.

[24] Abou-Arab O, Kamel S, Beyls C, Huette P, Bar S, Lorne E, et al. Vasoplegia after cardiac surgery is associated with endothelial glycocalyx alterations. J Cardiothorac Vasc Anesth 2019. http://dx.doi.org/10.1053/j.jvca.2019.09.004.

[25] Huette P, Moussa MD, Beyls C, Guinot P-G, Guilbart M, Besserve P, et al. Association between acute kidney injury and norepinephrine use following cardiac surgery: a retrospective propensity score-weighted analysis. Ann Intensive Care 2022;12:61. http://dx.doi.org/10.1186/s13613-022-01037-1.

[26] Canty DJ, Kim M, Royse CF, Andrews D, Botrell S, Royse A. The impact of routine norepinephrine infusion on hemodilution and blood transfusion in cardiac surgery. J Anesth Clin Res 2013;4:2.

[27] Huette P, Guinot P-G, Beyls C, Goldberg E, Guilbart M, Dupont H, et al. Norepinephrine exposure and acute kidney injury after cardiac surgery under cardiopulmonary bypass: a post-hoc cardio trial analysis. J Clin Anesth 2022;83110972. http://dx.doi.org/10.1016/j.jclinane.2022.110972.

[28] Lim JY, Park SJ, Kim HJ, Kim HJ, Choo SJ, Chung CH, et al. Comparison of dopamine versus norepinephrine in circulatory shock after cardiac surgery: a randomized controlled trial. J Card Surg 2021;36:3711-8. http://dx.doi.org/10.1111/jocs.15861.

[29] Guinot P-G, Abou-Arab O, Guilbart M, Bar S, Zogheib E, Daher M, et al. Monitoring dynamic arterial elastance as a means of decreasing the duration of norepinephrine treatment in vasoplegic syndrome following cardiac surgery: a prospective, randomized trial. Intensive Care Med 2017;43:643-51. http://dx.doi.org/10.1007/s00134-016-4666-z.

[30] Guinot P-G, Martin A, Berthoud V, Voizeux P, Bartamian L, Santangelo E, et al. Vasopressor-sparing strategies in patients with shock: a scoping-review and an evidence-based strategy proposition. J Clin Med 2021;10:3164. http://dx.doi.org/10.3390/jcm10143164.

[31] Morisson L, Duceau B, Do Rego H, Lancelot A, Hariri G, Charfeddine A, et al. A new machine learning algorithm to predict veno-arterial ECMO implantation after post-cardiotomy low cardiac output syndrome. Anaesth Crit Care Pain Med 2022;42101172. http://dx.doi.org/10.1016/j.accpm.2022.101172.

[32] Joannidis M, Druml W, Forni LG, Groeneveld ABJ, Honore PM, Hoste E, et al. prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the working group on prevention, AKI section, European society of intensive care medicine. Intensive Care Med 2017;43:730-49. http://dx.doi.org/10.1007/s00134-017-4832-y.

[33] Mertes P-M, Kindo M, Amour J, Baufreton C, Camilleri L, Caus T, et al. Guidelines on enhanced recovery after cardiac surgery under cardiopulmonary bypass or off-pump. Anaesth Crit Care Pain Med 2022;41101059. http://dx.doi.org/10.1016/j.accpm.2022.101059.
[9] Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA, et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology 2017;126:85-93. http://dx.doi.org/10.1097/ALN.00000000000001434.

[10] Toulouse E, Granier S, Nicolas-Robin A, Bahans C, Milman A, Andrieu VR, et al. The French clinical research in the European Community regulation era. Anaesth Crit Care Pain Med 2022;42101192. http://dx.doi.org/10.1016/j.accpm.2022.101192.

[11] Doussau A, Perez P, Puntous M, Calderon J, Jeanne M, Germain C, et al. Fresh-frozen plasma transfusion did not reduce 30-day mortality in patients undergoing cardiopulmonary bypass cardiac surgery with excessive bleeding: the PLASMACARD multicenter cohort study. Transfusion (Paris) 2014;54:1114-24. http://dx.doi.org/10.1111/trf.12422.

[12] Abou-Arab O, Huette P, Martineau L, Beauvalot C, Beyls C, Josse E, et al. Hyperoxia during cardiopulmonary bypass does not decrease cardiovascular complications following cardiac surgery: the CARDIOX randomized clinical trial. Intensive Care Med 2019;45:1413-21. http://dx.doi.org/10.1007/s00134-019-05761-4.

[13] Guinot P-G, Ellouze O, Grosjean S, Berthoud V, Constandache T, Radhouani M, et al. Anaesthesia and ICU sedation with sevoflurane do not reduce myocardial injury in patients undergoing cardiac surgery: a randomized prospective study. Medicine (Baltimore) 2020;99e23253. http://dx.doi.org/10.1097/MD.000000000000023253.

[14] Jammer I, Wickboldt N, Sander M, Smith A, Schultz MJ, Pelosi P, et al. Standards for definitions and use of outcome measures for clinical effectiveness research in perioperative medicine: European perioperative clinical outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on perioperative outcome measures. Eur J Anaesthesiol 2015;32:88-105. http://dx.doi.org/10.1097/EJA.00000000000000118.

[15] Schulte PJ, Mascha EJ. Propensity score methods: theory and practice for anesthesia research. Anesth Analg 2018;127:1074-84. http://dx.doi.org/10.1213/ANE.00000000000002920.

[16] Vail EA, Shieh M-S, Pekow PS, Gershengorn HB, Walkey AJ, Lindenauer PK, et al. Use of vasoactive medications after cardiac surgery in the United States. Ann Am Thorac Soc 2021;18:103-11. http://dx.doi.org/10.1513/AnnualATS.202005-4650C.

[17] García PS, Brown CHIV. Phenylephrine or ephedrine for intraoperative hypotension? Consider the cerebral microcirculation. Anesthesiology 2021;135:775-7. http://dx.doi.org/10.1097/ALN.00000000000003975.

[18] Gao F, Zhang Y. Inotrope use and intensive care unit mortality in patients with cardiogenic shock: an analysis of a large electronic intensive care unit database. Front Cardiovasc Med 2021;8696138. http://dx.doi.org/10.3389/fcvm.2021.696138.

[19] Bastopcu M, Sargin M, Kuplay H, Erdoğan SB, Yapıcı N, Aka SA. Risk factors for vasoplegia after coronary artery bypass and valve surgery. J Card Surg 2021;36:2729-34. http://dx.doi.org/10.1111/jocs.15663.

[20] Dayan V, Cal R, Giangrossi F. Risk factors for vasoplegia after cardiac surgery: a meta-analysis. Interact Cardiovasc Thorac Surg 2019;28:838-44. http://dx.doi.org/10.1093/icvts/ivy352.

[21] POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet Lond Engl 2008;371:1839-47. http://dx.doi.org/10.1016/S0140-6736(08)60601-7.

[22] Lominadze D, Dean WL, Tyagi SC, Roberts AM. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease. Acta Physiol Oxf Engl 2010;198:1-13. http://dx.doi.org/10.1111/j.1748-1716.2009.02037.x.

[23] Harrison DG, Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: implications for impaired vasomotion. Am J Cardiol 1995;75:75B-81B. http://dx.doi.org/10.1016/0002-9149(95)80018-n.

[24] Abou-Arab O, Kamel S, Beyls C, Huette P, Bar S, Lorne E, et al. Vasoplegia after cardiac surgery is associated with endothelial glycocalyx alterations. J Cardiothorac Vasc Anesth 2019. http://dx.doi.org/10.1053/j.jvca.2019.09.004.

[25] Huette P, Moussa MD, Beyls C, Guinot P-G, Guilbart M, Besserve P, et al. Association between acute kidney injury and norepinephrine use following cardiac surgery: a retrospective propensity score-weighted analysis. Ann Intensive Care 2022;12:61. http://dx.doi.org/10.1186/s13613-022-01037-1.

[26] Canty DJ, Kim M, Royse CF, Andrews D, Botrell S, Royse A. The impact of routine norepinephrine infusion on hemodilution and blood transfusion in cardiac surgery. J Anesth Clin Res 2013;4:2.

[27] Huette P, Guinot P-G, Beyls C, Goldberg E, Guilbart M, Dupont H, et al. Norepinephrine exposure and acute kidney injury after cardiac surgery under cardiopulmonary bypass: a post-hoc cardio trial analysis. J Clin Anesth 2022;83110972. http://dx.doi.org/10.1016/j.jclinane.2022.110972.

[28] Lim JY, Park SJ, Kim HJ, Kim HJ, Choo SJ, Chung CH, et al. Comparison of dopamine versus norepinephrine in circulatory shock after cardiac surgery: a randomized controlled trial. J Card Surg 2021;36:3711-8. http://dx.doi.org/10.1111/jocs.15861.

[29] Guinot P-G, Abou-Arab O, Guilbart M, Bar S, Zogheib E, Daher M, et al. Monitoring dynamic arterial elastance as a means of decreasing the duration of norepinephrine treatment in vasoplegic syndrome following cardiac surgery: a prospective, randomized trial. Intensive Care Med 2017;43:643-51. http://dx.doi.org/10.1007/s00134-016-4666-z.

[30] Guinot P-G, Martin A, Berthoud V, Voizeux P, Bartamian L, Santangelo E, et al. Vasopressor-sparing strategies in patients with shock: a scoping-review and an evidence-based strategy proposition. J Clin Med 2021;10:3164. http://dx.doi.org/10.3390/jcm10143164.

[31] Morisson L, Duceau B, Do Rego H, Lancelot A, Hariri G, Charfeddine A, et al. A new machine learning algorithm to predict veno-arterial ECMO implantation after post-cardiotomy low cardiac output syndrome. Anaesth Crit Care Pain Med 2022;42101172. http://dx.doi.org/10.1016/j.accpm.2022.101172.

[32] Joannidis M, Druml W, Forni LG, Groeneveld ABJ, Honore PM, Hoste E, et al. prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the working group on prevention, AKI section, European society of intensive care medicine. Intensive Care Med 2017;43:730-49. http://dx.doi.org/10.1007/s00134-017-4832-y.

[33] Mertes P-M, Kindo M, Amour J, Baufreton C, Camilleri L, Caus T, et al. Guidelines on enhanced recovery after cardiac surgery under cardiopulmonary bypass or off-pump. Anaesth Crit Care Pain Med 2022;41101059. http://dx.doi.org/10.1016/j.accpm.2022.101059.