Microcirculatory effects of cardiopulmonary bypass primings in coronary artery bypass graft surgery the prime randomised clinical trial for a physiological proof-of-principle

Abstract

Objectives

Cardiopulmonary bypass (CPB) impairs endothelial function, causing oedema and disturbed microcirculatory perfusion, that contribute to organ dysfunction following cardiac surgery. We hypothesised that the composition of CPB prime fluids with either albumin or gelofusine preserves sublingual microcirculatory perfusion in patients undergoing coronary artery bypass graft surgery.

Methods

Thirty-four patients were subjected to CPB primed with 1500 ml of either albumin/ringers (n = 8, gelofusine/ringers (n = 11), or solely ringers plus retrograde autologous priming (RAP) (n = 15). All solutions included 100 ml of mannitol. The primary outcome was perfused vessel density (PVD) assessed after anaesthesia induction, aortic cross-clamping, weaning from CPB, upon intensive care unit (ICU) arrival and 24 h after ICU arrival.

Results

CPB immediately impaired PVD across all groups, persisting until ICU arrival. The decrease in PVD was most profound with albumin/ringers (estimated mean difference between baseline and ICU arrival −7.56 [95% CI -11.53 to −3.59] mm^.mm^-2), compared to gelofusine/ringers (−4.10 [−7.53 to −0.67] mm^.mm^-2), and ringers/RAP (−3.77 [-6.64 to −0.90] mm^.mm^-2), without differences between groups (p = 0.41). In patients receiving gelofusine/ringers COP was preserved after aortic cross clamping. Concentration of inflammatory (interleukin-6) and endothelial damage markers (angiopoietin-2) were increased with albumin/ringers compared with gelofusine/ringers and ringers plus RAP.

Conclusion

In this exploratory physiological study, all of the three CPB priming strategies, albumin/ringers, gelofusine/ringers or ringers plus RAP, similarly induced perioperative microcirculatory dysfunction in patients undergoing CABG surgery.

Keywords

microcirculation colloid crystalloid glycocalyx colloid oncotic pressure

Introduction

Cardiac surgery with cardiopulmonary bypass (CPB) increases the risk for organ dysfunction, particularly renal, myocardial and lung injury, which are associated with increased morbidity and mortality.^1–3 Microcirculatory perfusion decreases by 20% from the onset of CPB,⁴ and is caused by increased endothelial permeability and vascular leakage, both consequences of systemic inflammation, endothelial activation, haemodilution and haemolysis.^5–9 Since, these disturbances occur immediately upon CPB initiation, the choice of CPB prime fluid composition may be crucial.

Typically, CPB prime fluids are composed of crystalloids, occasionally combined with colloids to enhance colloid oncotic pressure (COP) and viscosity,¹⁰ though, the optimal composition remains debated. Albumin has been shown some advantages over solely crystalloids in preserving COP, reducing oedema and decreasing the risk of myocardial injury.^11–13 In rats on CPB, albumin reduces pulmonary oedema, renal injury, inflammation and glycocalyx degradation compared to hydroxyethyl starch (HES).¹⁴

However, despite its high COP,¹⁵ HES was withdrawn because of safety concerns regarding increased risk of renal injury. Gelofusine, a less expensive synthetic colloid, has not been studied for its effects on the microcirculation. Furthermore, retrograde autologous priming (RAP), designed to reduce net priming volume, reduces transfusions, but its ability to maintain COP and its effects on the microcirculation remains unclear.¹⁶

This study, designed as an exploratory physiological proof-of-principle, aimed to compare the effects of albumin/ringers, gelofusine/ringers, or ringers plus RAP as CPB prime fluid strategies on microcirculatory perfusion in patients undergoing on-pump coronary artery bypass graft surgery (CABG). We hypothesized that either albumin/ringers or gelofusine/ringers would maintain microcirculatory perfusion compared to ringers plus RAP as CPB priming.

Methods

Study design

This single-centre, double-blind randomised clinical trial was conducted at the Amsterdam University Medical Center in the Netherlands. The ethics committee approved the study protocol on April 17^th, 2023, which has been published previously,¹⁷ and approved the amendment on May 30^th, 2024. This study was registered at clinicalTrials.gov (registered on April 25, 2023, ClinicalTrials.gov PRS: Record Summary NCT05647057). The manuscript was prepared in accordance with the CONSORT guidelines (EQUATOR network), with a checklist included.¹⁸

Patients

The trial enrolled adult patients receiving CABG surgery with CPB. Exclusion criteria were emergency surgery, aortic surgery, valve surgery, combined procedures valve and CABG surgery, known allergy for human albumin or gelofusine, and the use of crystalloid cardioplegia. Written informed consent was obtained from all patients.

Interventions

Patients were randomised to receive either (1) 1500 ml of gelofusine/ringers (750 ml modified fluid gelatin 4%, 650 ml ringers solution and 100 ml mannitol 15%); (2) 1500 ml of albumin/ringers (1200 ml ringers solution, 200 ml human albumin 20% and 100 ml mannitol 15%), or (3) 1500 ml of ringers plus RAP (1400 ml ringers solution and 100 ml mannitol 15% with RAP). Volumes of 20% albumin and 4% modified gelatin were chosen based on their molecular weight, osmolarity, intravascular retention, and practical clinical considerations.¹⁹ Volume losses were replaced using Plasmalyte in all groups. Apart from the intervention, no additional colloid fluids were administered in the perioperative process. Randomisation and blinding are described in Supplemental Material Appendix S2.

Outcomes

The primary outcome was the change in perfused vessel density (PVD), reflecting microcirculatory diffusion capacity, collected using a sidestream dark field (SDF) video microscopy (USB3, Microvision Medical, Amsterdam, The Netherlands), at five consecutive time points: after anaesthesia induction, after aortic cross clamping, after weaning from CPB, after arrival on the ICU and 24 h after ICU arrival. The technique of microcirculatory assessment and analyses method is described in Supplementary Materials Appendix S3 and Table S2.

Secondary outcomes included total vessel density (TVD), proportion of perfused vessels (PPV), heterogeneity index, microvascular flow index (MFI), COP, albumin, markers for glycocalyx shedding, endothelial function, inflammation and renal injury: syndecan-1, heparan sulphate, thrombomodulin, angiopoietin-2 (Ang-2), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL), haemoglobin, haematocrit, haemolysis index, noradrenaline infusion dose during each measurement, transfusions, fluid balance and fluid requirements. Details regarding the anaesthesia and CPB protocol, including RAP and biomarker analyses are provided in Supplementary Materials Appendix S3.

Sample size calculation and statistical analysis

To date, there have been no interventional studies investigating the effects of priming on microcirculatory perfusion during CPB. Therefore, no reliable estimates of the expected effect sizes were available to guide our sample size calculation. The assumptions were therefore based on observational data describing the decline in PVD during CPB. Specifically, a decrease in PVD from induction of anaesthesia to CPB initiation of 5 mm.mm‾², with a standard deviation (SD) of 4 mm^.mm^-2, was used as the reference.^20–22 Based on these assumptions, a sample size of 24 patients (8 patients per group) would provide 80% power to detect a maximal decrease in PVD of 5 mm^.mm^-2 (SD 4), with a two-sided α of 0.05, across three groups and five consecutive measurement points. To account for an anticipated dropout rate of 20%, thirty patients were enrolled (10 per group). Secondary outcomes were considered exploratory and were not subject to a formal sample size calculation.

The primary analysis was conducted according to a per-protocol principle. This analysis excluded patients who received fluids other than those specified in the study protocol, as well as patients with insufficient quality microcirculation imaging for analysis of the primary outcome. For the primary analysis, changes in PVD between groups over time were compared using linear mixed effects models, with time and group included as a fixed effect and patient as a random effect. The interaction between time and group was included in the model to assess whether the PVD changes differed across groups over time. When a significant overall between-group difference was observed, pairwise comparisons of the means at different time points were performed. To account for multiple testing across the three groups and five time points, Bonferroni-adjusted significance thresholds were applied, maintaining an overall α of 0.05. The use of the Bonferroni correction was necessary due to the substantial multiplicity introduced by the multiple comparisons, and the correction method was applied directly in the linear mixed effects models through pairwise comparisons in R. However, results from these pairwise comparisons should be interpreted as exploratory, as the primary outcome was based on the overall between-group difference over time. Depending on the pattern and mechanism of missing data, either complete case analysis was applied (if missing completely at random), or multiple imputation was considered (if missing at random). Missing data were not imputed if, from a physiological point of view, it was assumed that the values were missing at random, e.g., due to temporary technical artifacts or the refusal of patients who were not involved in the intervention to undergo microcirculation measurement while awake.

Data were expressed as percentages (%), as mean ± SD or median [IQR] in case of non-normally distributed variables. Normality was checked by means of normal-probability plots (boxplot, Q-Q plot) and the Kolmogorov Smirnov and Shaprio-Wilk tests. Secondary outcome over time were compared between groups using linear mixed effect models. If a difference was found, means for different time points were compared with pairwise comparisons, as described for the primary outcome. For comparison of normally distributed continuous variables, means were compared using one-way ANOVA. For comparison of continuous non-normally distributed variables medians were compared using the Kruskal-Wallis test. Categorical variables were compared by chi-square or Fisher’s exact test as appropriate. R version 4.3.2 (R, Vienna, Austria) was used for all statistical analyses.

Results

Patients

Patients were recruited from July 10^th 2023, to July 8^th 2024. 62 patients were eligible for study participation. In total 48 patients were randomised, 13 patients were replaced because of changes in date of surgery, which resulted in the use of crystalloid cardioplegia instead of autologous warm-blood cardioplegia (n = 8), or in surgical procedure (off-pump n = 4; percutaneous coronary intervention n = 1). One patient was excluded from the final analysis as a result of inadequate microcirculation imaging quality scoring. 34 patients were included in the final analysis (Figure 1 and Supplemental Material Table S1). More information on randomisation can be found in the Supplemental Material Appendix S2. Baseline characteristics were comparable between the study groups (Table 1).

Figure 1.

Flowchart of included patients.

Table 1.

Patient and operative characteristics.

	Albumin/ringers (n = 8)	Gelofusine/ringers (n = 11)	Ringers/RAP (n = 15)
Sex, male, n (%)	6 (75)	9 (81)	15 (100)
Age, yr, median [IQR]	66 [63–71]	61 [58–76]	70 [64–74]
BMI, kg m^-2, median [IQR]	27.8 [24.5–29.1]	26.9 [25.7–28.5]	27.9 [26.7–29.1]
BSA, m², median [IQR]	2.0 [1.9–2.1]	2.0 [1.8–2.1]	2.1 [2–2.2]
EuroSCORE II, median [IQR]	0.99 [0.99–0.99]	0.99 [0.99-1.48]	0.99 [0.99–1.48]
Comorbidities, n (%)
Current smoker	2 (25)	1 (9)	2 (13)
Renal impairment*	1 (13)	0	0
Pulmonary disease	1 (13)	0	0
Peripheral vascular disease	1 (13)	0	2 (13)
Diabetes mellitus
Type II on insulin	0	3 (27)	1 (7)
Type II without insulin	1 (12)	1 (9)	4 (27)
Preoperative lab, median [IQR]
Haemoglobin, mmol^.L^-1	8.4 [8.2–9.4]	8.9 [8.2–9.2]	8.6 [8.4–9.0]
Platelet count, 10^9.L^-1	272 [198–287]	197 [178–316]	215 [201–256]
eGFR, ml^.min^-1.1.73 m^-2	81 [75–88]	89 [72–90]	84 [72–90]
Preoperative antiplatelet therapy, n (%)
Acetylsalicylic acid	4 (50)	10 (91)	13 (87)
Carbasalate calcium	1 (13)	1 (9)	2 (13)
DAPT	2 (25)	0	0
Operative characteristics
Total surgery time, median [IQR]	254 [233–306]	258 [225–282]	246 [218–288]
CPB time, min, median [IQR]	92 [73–100]	78 [67–103]	84 [72–106]
AoX time, min, median [IQR]	68 [45–87]	56 [47–67]	54 [49–79]
Blood cardioplegia, mmol, median [IQR]	31 [26–35]	28 [28–30]	30 [28–33]

ASA, American Society of Anesthesiologists; AoX, aortic cross clamping; BMI, Body Mass Index; BSA, Body Surface Area; CPB, Cardiopulmonary Bypass; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; EuroSCORE II, European System for Cardiac Operative Risk Evaluation II.

^*Renal impairment is characterised as known chronic kidney disease preoperatively.

Perfused vessel density

The PVD was comparable between groups at baseline (median 23.8 [IQR 19.9–27.1] mm^.mm^-2; 20.1 [17.6–25.2] mm^.mm^-2; and 21.6 [19.3–24.4] mm^.mm^-2 for patients in the albumin/ringers, gelofusine/ringers and ringers plus RAP group) (Figure 2). PVD decreased after aortic cross clamping in all groups and remained disturbed upon arrival in the ICU. The decrease in PVD was most profound in patients receiving albumin/ringers priming (estimated mean difference between baseline and arrival ICU -7.56 [95% CI -11.53 to −3.59] mm^.mm^-2), compared to gelofusine/ringers (−4.10 [−7.53 to −0.67] mm^.mm^-2) and ringers plus RAP (−3.77 [−6.64 to −0.90] mm^.mm^-2), but did not differ between groups (p = 0.41).

Figure 2.

Microcirculatory parameters. Data presented as medians with interquartile ranges. Statistical significance value, p <0.05. Abbreviations: AoX, aortic cross clamping; CPB, cardiopulmonary bypass; ICU, intensive care unit; MFI, microvascular flow index; PVD, perfused vessel density; PPV, proportion of perfused vessels; TVD, total vessel density.

Secondary outcomes

Microcirculatory perfusion or the noradrenaline infusion dose did not differ between groups over time. COP decreased after aortic cross clamping in the albumin/ringers and ringers plus RAP group but was preserved in the gelofusine/ringers group. Plasma albumin decreased over time, but remained highest in patients receiving albumin/ringers. Haemoglobin concentrations were slightly higher in patients receiving ringers plus RAP priming, compared with albumin/ringers and gelofusine/ringers (Figure 3). Intraoperative fluid requirements and fluid balances were increased in patients receiving albumin/ringers and ringers plus RAP, compared with gelofusine/ringers (Table 2). Ang-2 and IL-6 were increased in patients receiving albumin/ringers at 24 h after ICU admission, compared to those receiving ringers plus RAP. Concentrations of NGAL were different between groups over time (Figure 4 and Table S4).

Figure 3.

Plasma COP, Albumin, Haemoglobin, Haematocrit and Haemolysis levels.Data presented as median with interquartile range. Data presented as median with interquartile range. Statistical significance value, p <0.05. Abbreviations: AoX, aortic cross clamping; CPB, cardiopulmonary bypass; COP, colloid oncotic pressure; ICU, intensive care unit.

Table 2.

Secondary outcomes.

	Albumin/ringers (n = 8)	Gelofusine/ringers (n = 11)	Ringers/RAP (n = 15)	p-value
Intraoperative fluids, ml, median [IQR]
Total prime volume	1500 [1500–1500]	1500 [1500–1500]	1500 [1500–1500]	‐
RAP	0	0	400 [325–450]	<.001
Additional fluids	1216 [1000–1450]	889 [500–1045]	1700 [1204-1958]	0.005
Sodium bicarbonate	0 [0-65]	0	0	0.23
RBC transfusion	0	0	0	‐
Platelet transfusion	0	0	0	‐
Fresh frozen plasma	0	0	0	‐
Cell saver volume	434 [337–613]	510 [413–567]	418 [248–481]	0.23
Fluid balance	1641 [1535–1728]	801 [543–1030]	2075 [1719–2270]	0.002
Fluids after surgery, ml, median [IQR]
RBC transfusion	0	0	0	‐
Platelet transfusion	0	0	0	‐
Fresh frozen transfusion	0	0	0	‐
Blood loss 24 h postoperative	818 [648–1168]	590 [508–748]	600 [515–735]	0.19
Complications after surgery
ECMO, n (%)	0	0	0	‐
Acute kidney injury, n (%)*	0	0	0	‐
Pneumonia, n (%)	1 (13)	0	1 (7)	0.71
Cerebrovascular accident, n (%)	0	0	0	‐
New onset atrial fibrillation, n (%)	2 (25)	1 (9)	5 (33)	0.34
Myocardial infarction, n (%)	1 (13)	0	0	0.24
Other complications, n (%)	2 (25)	1 (9)	3 (20)	0.73
Re-operation, n (%)	2 (25)	0	1 (7)	0.16
ICU length of stay, hours, median [IQR]	24 [22–59]	22 [21–24]	23 [21–25]	0.33
Hospital stay, days, median [IQR]	4 [3–7]	3 [3–5]	4 [3–7]	0.42

Abbreviations: ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; RAP, retrograde autologous priming; RBC, red blood cells.

*acute kidney injury, defined on the creatinine levels of the KDIGO guidelines.³⁴

Figure 4.

Plasma Biomarkers. Data presented as median with interquartile range. Statistical significance value, p <0.05. Abbreviations: AoX, aortic cross clamping; CPB, cardiopulmonary bypass; ICU, intensive care unit; IL-6, interleukin-6; NGAL, neutrophil gelatinase-associated lipocalin.

Discussion

Our study was designed as an exploratory physiological proof-of-principle study to evaluate the effect of CPB priming on microcirculatory perfusion. In patients undergoing CABG surgery with CPB, all investigated prime fluid strategies, albumin/ringers, gelofusine/ringers or ringers plus RAP, similarly induced microcirculatory perfusion disturbances. Gelofusine/ringers better maintained COP during CPB, and decreased intraoperative fluid balances and fluid requirements. In addition, albumin/ringers increased plasma levels of Ang-2 and IL-6 24 h after ICU admission.

This study has several strengths. It was designed as an exploratory physiological proof-of-principle study to evaluate the effect of CPB priming on microcirculatory perfusion, conducted by a team with extensive experience in microcirculatory perfusion assessment. The findings from our previous study, in which we evaluated the effects of CPB priming on microcirculatory perfusion in an animal model, were incorporated into the PRIME.¹⁴ To minimize inter-investigator variability, all investigators performing microcirculatory assessments received training and followed the European guidelines for sublingual microcirculation assessment.²³

The observed decline in microcirculatory perfusion during CPB is consistent with previous studies.^4,9,24 However, while studies in patients with sepsis and in animals with hemorrhagic shock^25–28 suggest that colloids such as albumin or gelofusine preserve microcirculatory perfusion better than crystalloids, our study did not show any preservation of microcirculatory perfusion in the context of CPB.

Contrary to our hypothesis, patients who received albumin/ringers showed increased endothelial damage and inflammation markers following cardiac surgery than patients who received Gelofusine/ringers and ringers plus RAP. Since our study was not designed to detect differences in endothelial function, glycocalyx detachment, or inflammation, these findings should be considered preliminary. Furthermore, the administration of heparin may have interfered with the measurement of heparan sulfate levels using ELISA. Even after reversal with protamine, residual interference may remain due to interindividual variability in heparin clearance. Although microcirculatory dysfunction after sepsis and CPB shares several key mechanisms (e.g., systemic inflammation, glycocalyx degradation, and increased vascular permeability), a possible difference may lie in hemodilution at the start of CPB.^7,24,29 While moderate haemodilution is often well tolerated through compensatory mechanisms, severe haemodilution of CPB priming may become pathophysiological, compromising microcirculatory function.^8,30

In this study, COP was better maintained in patients receiving Gelofusine/ringers compared than in patients receiving albumin/ringers or ringers plus RAP. Better preservation of COP was paralleled by decreased intraoperative fluid requirements and fluid balances. Intraoperative fluid requirements, fluid balances and haemoglobin concentration were slightly higher in patients receiving ringers plus RAP, compared with those receiving albumin/ringers or gelofusine/ringers. The increased fluid requirements and balances may reflect greater interstitial fluid accumulation, while the higher hemoglobin concentrations likely relate to the hemoglobin-preserving effect of RAP. Although RAP contributes to maintaining hemoglobin and reducing hemodilution, the physiological relevance of COP preservation appears limited under the conditions of this study. Increased fluid balances and requirements might indicate potential differences in microcirculatory behavior between the groups, though microcirculatory perfusion was equally disturbed. The impact of haemodilution may play a greater role than the composition of CPB priming in affecting microcirculatory perfusion. A previous study showed that using a mini-CPB system better preserved microcirculatory perfusion compared to conventional CPB, suggesting that prime fluid composition might be overshadowed by the impact of haemodilution at CPB initiation, a key factor attributing to microcirculatory impairment.^8,31 Finally, the standardization of key physiological parameters, including CPB-flow, ranges of mean arterial pressures during CPB, temperature, and FiO₂, in conjunction with comparable noradrenaline doses suggests that microcirculatory conditions were largely comparable between groups.

We observed a rise in IL-6 in patients receiving albumin/Ringers, for which we do not have a definitive explanation. Patients with NSTEMI, who are known for a proinflammatory state, were comparable between groups. Hemolysis, which can increase IL-6,³² also did not differ. Surgical procedures and CPB duration were also comparable across groups. Therefore, we suspect that the observed increase possibly reflects redistribution of IL-6 into the plasma rather than a true difference in inflammatory response.³³ Given the lack of power for formal hypothesis testing and multiple comparisons, the findings of secondary outcomes should be considered exploratory and hypothesis-generating.We would like to point out the following limitations that should be taken into account when interpreting our results. This study was a single-center study involving patient undergoing CABG surgery, which limits the generalizability of the results to some degree. RAP was performed only in the prime composition consisting solely of ringers. Patients receiving Patients who received ringers solution plus RAP experienced less initial hemodilution compared to other groups, which may have influenced our results. Despite, the RAP volume being displaced during CPB in all patients, causal interpretations should therefore be made cautiously. The generalizability of our findings may be somewhat limited, as no intraoperative transfusions were required while using cell saver volume, reflecting local practices that may differ in other centers. Furthermore, apart from continuous noradrenaline infusion, no other continuous vasopressors were administered. Short-acting boluses were only incidentally administered. Thus, noradrenaline dose at each timepoint reflected the primary vasopressor support in all patients. Also, the random replacement of patients driven by logistical changes, may have introduced selection bias by disrupting the original randomization. Additionally, the use of random block sizes of three, six, and nine led to an uneven distribution of patients across the three study groups. Furthermore, the per-protocol analysis introduces selection bias due to post-randomization exclusion of patients. Although the change appears largely random (logistical), the analyzed cohort may differ slightly from the original randomized population. In addition, 24 h after admission to the intensive care unit, some data were missing (36% contained videos) due to technical problems or patient refusal, as patients perceived sublingual measurements while awake as burdensome. These missing data were assumed to be missing at random, and at all other time points, the data were largely complete (70–91% contained videos, Table S5). Although the group sizes were sufficient to detect physiological differences in microcirculatory perfusion, the small sample size combined with incomplete data at T5 may have limited the study’s power to detect modest but physiologically meaningful effects. The absence of statistically significant differences should not be interpreted as evidence of absence of a clinically meaningful effect.

It should be noted that our study was designed as an exploratory physiological proof-of-principle and is insufficient to correlate our findings on microcirculation physiology with clinical outcomes.

In summary, despite differences in laboratory and physiological markers, all priming fluids examined - albumin/ringers, gelofusine/ringers, or ringers plus RAP - similarly induced microcirculatory perfusion disturbances in patients undergoing CABG surgery with CPB. In this exploratory physiological study, there was no evidence to suggest that any of the investigated priming strategies examined was superior in maintaining microcirculatory perfusion during CPB, within the study’s limitations. Overall, this study underscores the multifactorial complexity of microcirculatory disturbances during cardiac surgery.

Supplemental material

Supplemental material - Microcirculatory effects of cardiopulmonary bypass primings in coronary artery bypass graft surgery the prime randomised clinical trial for a physiological proof-of-principle

Supplemental material for Microcirculatory effects of cardiopulmonary bypass primings in coronary artery bypass graft surgery the prime randomised clinical trial for a physiological proof-of-principle by Anne M. Beukers, Jord C. Seegers, Nikki van Haasteren, Meike Brouwers, Ruben J. Bosch, Anita M. Tuip-de Boer, Charissa E. van den Brom, Susanne Eberl, Floor J. Mansvelder, Gudrun Kunst, David M.P. van Meenen, Carolien S.E. Bulte, Stephan A. Loer, Alexander Vonkin in Perfusion

Footnotes

ORCID iDs

Anne M. Beukers

Nikki van Haasteren

Gudrun Kunst

Ethical considerations

The ethics committee of the Amsterdam University Medical Center approved the study protocol on April 17^th, 2023 with ethical approval number 2023.0036.

Consent to participate

Written informed consent was obtained from all patients.

Author’s contributions

AMB: conceptualization, funding acquisition, investigation, methodology, visualization, writing original draft, writing review & editing

JCS: data curation, formal analysis, investigation, visualization, writing review & editing

NvH: formal analysis, investigation, writing review & editing

MB: data curation, formal analysis, writing review & editing

RB: conceptualization, writing review & editing

AMTdB: formal analysis, investigation, writing review & editing

CEvdB: conceptualization, resources, writing review & editing

SE: writing review & editing

JM: interpretation, visualization, writing review & editing

GK: visualization, writing review & editing

DMPvM: visualization, writing review & editing

CSEB: conceptualization, investigation, supervision, writing review & editing

ABAV: conceptualization, investigation, methodology, supervision, writing review & editing

SAL: conceptualization, investigation, methodology, supervision, writing review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the European Society of Anaesthesiology and Intensive Care Andreas Hoeft grant (2024, ID ESAIC_GR_2024_AB) and the Amsterdam Cardiovascular Sciences Equipment Grant (2023).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.*

Supplemental material

Supplemental material for this article is available online.

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