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Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

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10.1038/s41598-024-71028-8
Article
Conservative fluid resuscitation protocol does not reduce the incidence of reoperation for bleeding after emergency CABG
Bruno Jowita 1
Varayath Mascha 2
Gahl Brigitta 3
Miazza Jules 3
Gebhard Caroline E. 14
Reuthebuch Oliver T. 34
Eckstein Friedrich S. 34
Siegemund Martin martin.siegemund@usb.ch

14
Hollinger Alexa 14
Santer David 34
1 grid.410567.1 0000 0001 1882 505X Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland
2 grid.410567.1 0000 0001 1882 505X Clinic for Anaesthesiology, University Hospital Basel, Basel, Switzerland
3 grid.410567.1 0000 0001 1882 505X Department of Cardiac Surgery, University Hospital Basel, Basel, Switzerland
4 https://ror.org/02s6k3f65 grid.6612.3 0000 0004 1937 0642 Medical Faculty of the University of Basel, Basel, Switzerland
9 9 2024
9 9 2024
2024
14 2103716 11 2023
23 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Reoperation for bleeding (ROB) after emergency coronary artery bypass grafting (eCABG) has been identified as an independent risk factor for mortality. Consecutively, the influence of fluid intake, fluid output, fluid balance, blood loss, and inotropic demand on ROB were analyzed. This retrospective single-center study included 265 patients undergoing eCABG between 2011 and 2020. From 2018, postoperative hemodynamic management was performed with lower volume administration and higher vasoactive support. The primary outcome measure was the incidence of ROB within 48 h according to altered fluid resuscitation strategy. Consecutively, the influence of fluid intake, fluid output, fluid balance, blood loss, and inotropic demand on ROB were analyzed. Incidence of ROB was independent from the volume resuscitation protocol (P = .3). The ROB group had a higher perioperative risk, which was observed in EuroSCORE II. Fluid intake (P = .021), fluid balance (P = .001), and norepinephrine administration (P = .004) were associated with ROB. Fluid output and blood loss were not associated with ROB (P = .22). Post-test probability was low among all variables. Although fluid management might have an impact on specific postoperative complications, different fluid resuscitation protocols did not alter the incidence of ROB after emergency CABG.

Trial registration: www.clinicaltrials.gov registration number NCT04533698; date of registration: August 31, 2020 (retrospectively registered due to nature of the study); URL: https://classic.clinicaltrials.gov/ct2/show/NCT04533698

Keywords

Cardiac surgery
Volume resuscitation protocol
Postoperative bleeding
Subject terms

Outcomes research
Medical research
issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Despite a reduction of hospitalisations cardiovascular diseases caused more deaths in the United States of America in 2020 than in 2019. The odds ratio of the increase in deaths per 100.000 for ischemic heart disease was 1.11 (95% CI 1.04–1.18) in 2020 versus 20191. While percutaneous coronary intervention (PCI) yields very good results in most patients with this disease, coronary artery bypass grafting (CABG) remains the gold standard in those with a high SYNTAX score2 as it significantly reduces the incidence of myocardial infarction, stroke, and the necessity of repeat revascularization, lowering mortality in many clinical scenarios3–5. Roughly 3% of all cases6 require emergency CABG due to ongoing ischemia, interventional complications, multivessel coronary artery disease, or anatomic unsuitability for PCI7,8. In patients with cardiogenic shock, the mortality of patients undergoing emergency CABG may be as high as 40%8. About 2–6% of patients undergoing CABG require reoperation for bleeding (ROB), which has been identified as an independent risk factor for mortality with an incidence of in-hospital death ranging from 9 to 22%9–12. In two thirds of all CABG cases, surgical site bleeding has been identified12. Patients with non-surgical site bleeding, diffuse bleeding, or microangiopathic bleeding seem to have worse outcomes11,12. Moreover, volume resuscitation with crystalloids, colloids, or erythrocytes may provoke dilutional coagulopathy with reduced levels of the majority of hemostatic elements, whereas fresh frozen plasma (FFP) transfusion dilutes corpuscular elements in the blood, but sustains soluble clotting factors at near normal levels13. According to in vitro experiments, the extent of dilution is proportional to the infused volume13, but this seems to be less clear for in vivo situations14. In addition, the mechanism of coagulopathy related to massive transfusion and hemodilution is not fully understood14. In general, evidence has emerged that a large positive fluid balance is associated with worse outcomes especially among patients with septic shock in intensive care15. In septic shock, but also in bleeding, volume resuscitation is rationalized by restoring circulating fluid volume and optimizing stroke volume. This understanding has led to a change of protocol for perioperative fluid resuscitation over the past decade with a shift from liberal to more restrictive management with the increased use of vasopressors to sustain blood pressure. This might reduce postoperative diluted coagulopathy16,17.

In this retrospective study, we hypothesized that the change from liberal to restrictive perioperative fluid management in emergency CABG has led to a significant reduction in ROB. Our primary aim was to determine whether the incidence and nature of ROB occurring during the first 48 h after index surgery changed in the years following the restrictive fluid resuscitation strategy. Our secondary aims were to quantify the association of fluid management (fluid intake, fluid output, fluid balance, blood loss, and inotropic support) with the outcome. To our knowledge, this is the first study to evaluate ROB in a non-elective CABG cohort.

Patients and methods

Study cohort

In this retrospective analysis, all patients who underwent emergency CABG at the University Hospital of Basel, Switzerland, between 2011 and 2020 were identified using our prospectively maintained quality management software (V1.7, Dendrite Clinical Systems Ltd, Reading, United Kingdom), which is regularly checked for completeness and consistency. Emergency CABG was defined as surgery within 12 h after diagnosis. Information including patient characteristics, inclusion criteria, risk factors, surgical details, and clinical outcomes was also obtained from this registry. Data from the intensive care unit (ICU), such as blood product demand, were obtained from anesthesia charts and from the patient data monitoring system (PDMS) (Metavision®, iMD Soft, Düsseldorf, Germany) of the ICU. Specifically, we extracted fluid resuscitation data on the amount and timing from PDMS using the hospital’s data-warehouse solution.

Clinical procedures

At our institution, isolated CABG procedures are performed with minimal extracorporeal circulation18. According to standard postoperative protocol, no heparin is administered during the first six hours after arrival at the ICU, and significant postoperative bleeding is defined as accumulative drainage output of 300 mL during the first postoperative hour or 400 mL during the first two postoperative hours. Indication for ROB is given with significant postoperative bleeding and represents a common decision of the intensivist together with the cardiac surgeon. Major adverse cardiac and cerebrovascular events (MACCE) are defined as myocardial ischemia or stroke.

Fluid management indicators and outcomes

The primary pre-specified fluid management indicator is cumulative fluid intake beginning at the end of surgery for 48 h or until ROB, whatever comes first. Secondary fluid management indicators include fluid output, fluid balance, blood loss, vasoactive support (i.e. norepinephrine or milrinone), and the vasoactive-inotropic score (VIS) at the end of surgery for 48 h or until ROB19. All indicator variables except for VIS (see statistics section for details) are cumulative in the same way as fluid intake.

For further exploration, fluid management variables (except for VIS) serve as indicators for management over shorter time intervals (e.g. cumulative hourly accumulation up to 12 h postoperatively).

The primary outcome (first study question) was ROB within 48 h following index eCABG surgery. Specifically, we considered surgery to be relevant for the following indications: (1) hemodynamic instability due to tamponade, or (2) any kind of intrathoracic bleeding or excessive blood drainage (> 300 mL/h, according to standard practice in the ICU of the University Hospital of Basel) with or without hemodynamic instability. All early reoperations were retrospectively assessed to achieve stringent outcome adjudication.

Secondary outcomes including fluid output, fluid balance, blood loss, inotropic support, and VIS were used to investigate the second study question (i.e. whether fluid management changed during observation period).

Statistics

The association of fluid management with the risk of early ROB applying liberal and restrictive approaches was analyzed. We first checked whether there was a crude association between the indicator variables fluid intake, fluid output, fluid balance, inotropic support (i.e. norepinephrine, milrinone), and VIS score and outcome by calculating odds ratios (OR) on tertiles, using the lowest tertile as reference. Non-parametric trends among tertiles were also investigated. In addition, logistic regressions were used to derive the odds of ROB associated with prognostic variables modelled as continuous variables. Sensitivity, specificity, area under the receiver operating characteristics curve (AUROC), and post-test probability for each possible cut-off value were also calculated, and the optimal cut-off according to the Youden-criterion was derived.

As an exploratory analysis, sensitivity, specificity, AUROC, post-test probability, and optimal cut-off of all prognostic variables cumulated (except for VIS) were calculated for a shorter accumulation time (e.g., ≤ 1 h, ≤ 2 h, … and ≤ 12 h).

To address whether fluid management changed over the years, we used median regression first including time as year of enrollment, then as a binary variable before 2018 vs. 2018 or later. We also checked whether frequency of outcome showed a change over the two time periods using logistic regression, including time in a similar way as for the continuous prognostic variables. The VIS score was calculated as the weighted cumulative dose of vasoactive medications a patient received per hour as described by Gaies et al.20 and the maximum dose among the first 12 h after surgery was selected.

We presented cumulative vasoactive treatment (medication and volume) and vasoactive treatment during ICU stay as binary (administered yes/no) and as amount neglecting zero. Further, these variables were pseudo-log-transformed (Reference: https://win-vector.com/2012/03/01/modeling-trick-the-signed-pseudo-logarithm/, accessed on May 8, 2022) and P values were calculated using Student’s t test, to exploit the quantitative information as good as possible given the zero inflation of these variables. In general, continuous variables, shown as medians and interquartile ranges, were compared using the Wilcoxon signed-rank test. Categorical variables are given as numbers with percentages. All analyses were carried out using Stata 16 (Stata Corp., College Station, TX, USA).

Disclosures

David Santer has received speaker honoraria and educational grants from Abbott and Medtronic, speaker honoraria from Abiomed, Nycomed GmbH and Zimmer GmbH, as well as research grants from Medtronic (Schweiz) AG, Mussler Medical Supply, Freiwillige Akademische Gesellschaft Basel, Mach-Gaensslen-Foundation and Fondation Andreas P. Naef pour la chirurgie thoracique. The other authors have nothing to disclose.

Results

Patient characteristics

A total of 265 patients who underwent eCABG were included in our analysis. Baseline characteristics are shown in Table 1, and intraoperative surgical details are shown in Supplemental Table 1. In total, ROB occurred in 21 of 265 patients (7.9%) forming the ROB group, while 244 patients served as the control group. Intraoperatively, cardiopulmonary bypass time was comparable, but aortic cross-clamp time was longer in ROB vs. control group patients (69 min [59–108] vs. 54 min [40–68]; P = .006). In-hospital mortality was markedly higher (29% vs. 7%; P = .005) in ROB versus controls. In addition, incidence of postoperative stroke (24% vs. 7.8%, P = .003), renal failure (43% vs. 11%, P < .001), renal replacement therapy (24% vs. 4.9%; P = .006), MACCE (52% vs. 13%; P < .001), as well as length of hospital-stay (18 vs. 10 days; P = .002) were increased in ROB patients (Table 2). Table 1 Patient characteristics.

	Total (n = 265)	Control (n = 244)	ROB (n = 21)	
Age, y	67 [61–74]	67 [61–74]	66 [62–75]	
Females	47 (18%)	45 (18%)	2 (10%)	
BMI, kg/m2	27 [24–30]	27 [24–30]	27 [25–30]	
Diabetes	79 (30%)	70 (29%)	9 (43%)	
CAD 3	226 (85%)	212 (87%)	14 (67%)	
Main stem disease	91 (34%)	80 (33%)	11 (52%)	
Peripheral artery disease	32 (12%)	29 (12%)	3 (14%)	
Preoperative stroke	27 (10%)	25 (10%)	2 (10%)	
Renal disease	13 (4.9%)	12 (4.9%)	1 (4.8%)	
Dialysis	3 (1.1%)	3 (1.2%)	0 (0.00%)	
COPD	31 (12%)	29 (12%)	2 (10%)	
Coagulation disorder	
 No	25 (9.4%)	22 (9.0%)	3 (14%)	
 Yes	235 (89%)	217 (89%)	18 (86%)	
 Unknown	5 (1.9%)	5 (2.0%)	0 (0.00%)	
Prior MI	246 (93%)	228 (93%)	18 (86%)	
Hypertension	209 (79%)	192 (79%)	17 (81%)	
Hypercholesteremia	157 (59%)	147 (60%)	10 (48%)	
NYHA III or IV	98 (37%)	88 (36%)	10 (48%)	
AF preop	16 (6.0%)	15 (6.1%)	1 (4.8%)	
Current smoker	68 (26%)	66 (27%)	2 (10%)	
Ejection fraction	50 [36–60]	50 [37–60]	50 [30–60]	
Hepatopathy	8 (3.0%)	7 (2.9%)	1 (4.8%)	
Dialysis	4 (1.5%)	4 (1.6%)	0 (0.00%)	
Peptic ulcer disease	5 (1.9%)	4 (1.6%)	1 (4.8%)	
Alcohol abuse	21 (7.9%)	20 (8.2%)	1 (4.8%)	
EuroSCORE II	5.9 [3.0–15]	5.7 [2.9–14]	14 [7.8–22]	
Preoperative patient characteristics. Continuous variables are given as median and interquartile range, categorical variables as number with percentage. AF, atrial fibrillation; BMI, body mass index; CAD 3, three-vessel coronary artery disease; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; NYHA: New York Heart Association; ROB, reoperation for bleeding within 48 after index surgery.

Table 2 Postoperative data.

	Total (n = 265)	Control (n = 244)	ROB (n = 21)	P value	
Operative mortality	23 (8.7%)	17 (7.0%)	6 (29%)	.005	
Length of ICU stay, days	3.0 [2.0–7.0]	3.0 [2.0–7.0]	10 [3.0–15]	.026	
Intubation > 72 h	25 (9.4%)	21 (8.6%)	4 (19%)	.12	
Postoperative MI	6 (2.3%)	6 (2.5%)	0 (0.00%)	1.00	
Postoperative stroke	24 (9.1%)	19 (7.8%)	5 (24%)	.030	
AF at discharge	78 (29%)	74 (30%)	4 (19%)	.33	
Permanent pacemaker	7 (2.6%)	7 (2.9%)	0 (0.00%)	1.00	
Sternal infection	15 (5.7%)	14 (5.7%)	1 (4.8%)	1.00	
Postoperative renal failure	35 (13%)	26 (11%)	9 (43%)	 < .001	
RRT	17 (6.4%)	12 (4.9%)	5 (24%)	.006	
Pulmonary infection	49 (18%)	42 (17%)	7 (33%)	.08	
MACCE	42 (16%)	31 (13%)	11 (52%)	 < .001	
Sepsis	11 (4.2%)	10 (4.1%)	1 (4.8%)	.60	
Length of in-hospital stay, days	11 [8.0–16]	10 [8.0–15]	18 [12–31]	.002	
Postoperative outcome. Continuous variables are given as median and interquartile range, categorical variables as number with percentage. AF, atrial fibrillation; ICU, intensive care unit; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; ROB, reoperation for bleeding within 48 h after index surgery, RRT: renal replacement therapy.

Change of volume resuscitation management

During the years of patient enrollment, cumulative fluid intake during the first 48 h after surgery or until ROB (whatever came first) decreased by 0.52 L per year on average, amounting to 3.15 L less after 2018 as compared to the period from 2011 to 2017. The amount of accumulated fluid output (expressed as negative values) also decreased slightly but consistently. Likewise, total fluid balance decreased by 0.35 L per year on average, amounting to 2.08 L less after 2018. The reductions in accumulated blood loss and fluid output were similar, as expected. No yearly trend was apparent for norepinephrine, but increased after 2018. Moreover, argipressin (Empressin®, OrPha Swiss, Küsnacht, Switzerland) as a second-line vasopressor, added to norepinephrine in shock treatment was introduced in 2018. Likewise, milrinone was administered more extensively during the later period. Nitroglycerin, administered rarely for vasodilation in arterial grafts, did not show a pattern. Maximum vasoactive inotropic score (VISmax)20 during the first 12 postoperative hours did not exhibit any change over time. ROB was equally frequent during the two periods and, therefore, was independent from the volume resuscitation protocol (Table 3). Table 3 Change of volume resuscitation management over time.

Variable	Time	Coefficient (95% CI)	P value for trend	
Fluid intake, 1000 mL	Per year	− 0.52 (− 0.74 to − 0.30)	 < .001	
Fluid intake, 1000 mL	 ≥ 2018	− 3.15 (− 4.45 to − 1.84)	 < .001	
Fluid output, 1000 mL	Per year	0.16 (0.03–0.29)	 < .001	
Fluid output, 1000 mL	 ≥ 2018	1.59 (0.85–2.33)	 < .001	
Fluid balance, 1000 mL	Per year	− 0.35 (− 0.52 to − 0.19)	 < .001	
Fluid balance, 1000 mL	 ≥ 2018	− 2.08 (− 2.93 to − 1.22)	 < .001	
Blood loss, 1000 mL	Per year	0.05 (0.02–0.08)	 < .001	
Blood loss, 1000 mL	 ≥ 2018	0.33 (0.12–0.54)	 < .001	
Norepinephrine, µg	Per year	− 23.6 (− 239 to 192)	.21	
Norepinephrine, µg	 ≥ 2018	1074 (− 435 to 2583)	.014	
Milrinone, µg	Per year	153 (− 57.9 to 365)	 < .001	
Milrinone, µg	 ≥ 2018	3103 (2269–3938)	 < .001	
Nitroglycerin, µg	Per year	Not calculable		
Nitroglycerin, µg	 ≥ 2018	Not calculable		
VISmax 12 h	Per year	− 0.16 (− 0.68 to 0.36)	.7	
VISmax 12 h	 ≥ 2018	0.59 (− 2.64 to 3.82)	.4	
ROB	Per year	0.99 (0.86–1.15)*	.9	
ROB	 ≥ 2018	1.57 (0.63–3.87)*	.3	
Change of volume variables per year. Postoperative volume resuscitation management was changed in 2018. *OR; ROB, reoperation for bleeding within 48 h after index surgery; VISmax 12 h, maximum vasoactive inotropic score within 12 h after index surgery.

Association of fluid intake and outcome

Fluid intake was higher in ROB compared to control group patients. However, there was a large overlap (Table 4). OR of overall increase was 1.07 (1.01–1.13) (P = .021), corresponding to an average increased risk of ROB by 0.5% for every 1000 mL fluid intake (overall risk of ROB: 7.9% (21 of 265 patients)). Tertiles of fluid intake did not show a trend towards higher ORs in higher categories (P = .6) (Supplemental Table 2). AUROC of fluid intake was 57% (43–72%), indicating no discriminative ability (Supplemental Table 3). The optimal cut-off of fluid intake was 17 432 mL (sensitivity 33%, specificity 90%, post-test probability 10%). Table 4 Variables of postoperative fluid resuscitation and inotropic support.

	Control (n = 244)	ROB (n = 21)	OR (95% CI)	P value	
Fluid intake, mL	10,228 [7512–13,280]	11,473 [8243–18,446]	1.07 (1.01–1.13)	.021	
Fluid output, mL	− 5683 [− 7073 to − 4078]	− 2765 [− 4250 to − 1645]	1.05 (0.89–1.23)	.6	
Fluid balance, mL	4710 [2715–6780]	7539 [5546–9763]	1.14 (1.05–1.23)	.001	
Blood loss, mL	− 1120 [− 1614 to − 740]	− 1300 [− 2120 to − 900]	0.71 (0.51–1.00)	.052	
Norepinephrine, µg	802 [0.00–5077]	6315 [3002–7749]	1.05 (1.01–1.08)	.004	
Milrinone, µg	0.00 [0.00–5943]	1447 [0.00–9113]	0.99 (0.94–1.04)	.7	
Nitroglycerin, µg	0.00 [0.00–470]	0.00 [0.00–0.00]	Not calculable		
VIS_max 12 h	6.1 [1.5–13]	17 [11–33]	1.07 (1.04–1.10)	 < .001	
Note that ORs were calculated by 1000 units to avoid digits, except for VIS_max 12 h. Continuous variables are given as median and interquartile range.

Association of secondary fluid management indicators and outcome

When comparing ROB with the control group patients, median accumulated fluid balance (OR of 1.14 per 1000 mL increase; P = .001) and norepinephrine demand (OR of 1.05 per 1000 µg, P = .004) were higher in ROB patients. In addition, the composite variable VISmax was markedly higher in ROB patients (OR of 1.07; P < .001). ORs for ROB did not increase with increasing tertiles of accumulated blood loss and milrinone. However, ORs were highest in the highest tertiles of fluid output, fluid balance, norepinephrine, and VISmax. Norepinephrine and VISmax12h showed the same pattern. Nitroglycerin was administered to 65 patients, none of whom underwent ROB. Data are shown in Table 4, Fig. 1, and Supplemental Table 2.Fig. 1 Intake, output, fluid balance and blood loss, use of norepinephrine and milrinone within 48 h after surgery.

To evaluate a clinical transferability of this study, fluids accumulated during the first 12 postoperative hours was use as a potential prognostic variable for ROB. Pre-test probability of bleeding was 8% (21 of 265 patients). The time point with highest area under the curve (AUC) was 6 h for fluid intake (sensitivity 71%, specificity 62%, AUC 69% (59–80)), 6 h for fluid output (sensitivity 57%, specificity 65%, AUC 64% (50–77)), 7 h for fluid balance (sensitivity 57%, specificity 71%, AUC 66% (53–78)), 5 h for blood loss (sensitivity 86%, specificity 72%, AUC 83% (73–92)), and 5 h for norepinephrine (sensitivity 86%, specificity 62%, AUC 79% (71–88)). VISmax 12 h reached a sensitivity of 86%, specificity of 66%, and AUC of 80% (72–88)). The highest calculated post-test probability was 21%, which was reached by blood loss at 5 h as well as norepinephrine at 4 h postoperatively (Supplemental Table 3).

Administration of blood products during index surgery and during the first 48 hours after ICU admission

Intraoperative administration of heparin and protamine as well as the activated clotting times (ACT) were comparable among groups (Supplemental Table 4). However, the ROB group received an additional dose of protamin (38% vs. 16%; P = .018) more often, due to insufficient correction of ACT after the first dose of protamine. The ROB group also received fibrinogen (Haemocomplettan®, CSL Behring AG, Bern, Switzerland) significantly more often (62% vs. 36%; P = .033). Markedly more patients in the ROB group received red blood cell (RBC) concentrates (86% vs. 39%; P < .001), fresh frozen plasma (FFP, 33% vs. 7.4%; P = .001), and platelets (57% vs. 25%; P = .004). While the documented intraoperative blood loss was significantly increased in the ROB group (900 mL [800–1500] vs. 800 mL [600–875]; P = .022), the total amount of cell saver retransfusion (autoLog IQ™, Medtronic (Schweiz) AG, Muenchenbuchsee, Switzerland; 371 mL [250–487] vs. 350 mL [250–487], not significant) was comparable in both groups. In addition, ROB group patients underwent open-chest treatment more often (38% vs. 2.9%; P < .001). In terms of intraoperative vasoactive support, the ROB group received significantly more norepinephrine (944 μg [360–4310] vs. 399 μg [153–878]; P = .004) and epinephrine (701 μg [331–2160] vs. 330 μg [183–613]; P = .013) during index surgery. Detailed data are shown in Supplemental Table 4. Markedly more ROB patients were treated with norepinephrine (100% vs. 68%; P < .001), epinephrine (86% vs. 55%; P = .005), argipressin (Empressin®, OrPha Swiss, Küsnacht, Switzerland; 4% vs. 1.2%; P = .007), and iloprost (Ventavis®, Bayer (Schweiz) AG, Zürich, Switzerland; 48% vs. 26%; P = .044) at the ICU. In addition, more ROB patients received RBC concentrates (100% vs. 52%; P < .001), FFP (86 vs. 33%; P < .001), platelets (71% vs. 18%, P < .001), and fibrinogen (67% vs. 16%; P < 0.001) compared to control group patients (Table 3).

Overall, more ROB patients received epinephrine (90% vs. 64%, P = .015), norepinephrine (100% vs. 76%; P = .006), and argipressin (19% vs. 2%; P = .003) intraoperatively and during the first 48 h after ICU admission. Further, significantly more ROB patients were treated with RBC concentrates (100% vs. 66%; P < .001), FFP (86% vs. 35%; P < .001), platelets (86% vs. 35%; P < .001), fibrinogen (90% vs. 47%; P < .001), and Haemate® P (von Willebrand factor concentrate, CSL Behring AG, Bern, Switzerland; 57% vs. 16%; P < .001) (Supplemental Tables 5 and 6).

Perioperative laboratory values

Laboratory values prior to index surgery revealed markedly lower levels of bicarbonate (20 mmol/L [19–22] vs. 23 mmol/L [21–25]; P = .003), increased lactate (2.0 mmol/L [1.3–5.1] vs. 1.2 mmol/L [0.9–1.7]; P = .009) as well as more negative base excess (− 7.2 mmol/L [-0.8 to − 2.8] vs. − 1.5 mmol/L [− 3.6 to − 0.10]; P = .002) in the ROB group. After CPB, ACTs were significantly higher in the ROB group (142 [129–161] vs. 129 [117–139] g/L; P = .007). Postoperative laboratory values showed lower bicarbonate (19 mmol/L [16–21] vs. 21 mmol/L [19–23]; P < .001), hemoglobin (87 g/L [76–96] vs. 95 g/L [87–104]; P = .005), fibrinogen (2.1 g/L [1.7–2.4] vs. 2.5 g/L [2.1–3.0]; P = .002) and base excess (− 9.2 mmol/L [− 11 to − 5.3] vs. − 3.6 mmol/L [− 5.9 to − 1.3]; P < .001), and increased international normalized ratio (INR; 1.4 [1.3–1.5] vs. 1.3 [1.2–1.4]; P = .016), creatinine (99 μmol/L [76–127] vs. 78 μmol/L [64–96]; P = .021), lactate (6.5 mmol/L [4.1–11] vs. 2.7 mmol/L [1.5–2.4]; P < .001), and activated partial thromboplastin time (aPTT; 46 s [38–66] vs. 32 s [29–36] s; P = .009) in ROB group patients (Supplemental Table 7).

Discussion

In this retrospective study, we analyzed the association of fluid management with the risk of ROB in 265 patients undergoing emergency CABG. Patients undergoing ROB were compared to a control group. First, the fluid management strategy (liberal vs. restrictive) had no influence on the incidence of ROB. Second, we were able to show that fluid intake, fluid balance, and norepinephrine demand were associated with ROB. However, a transfer of these associations into clinical practice failed. To our knowledge, this is the first study to evaluate volume resuscitation regimes in emergency CABG.

Mortality in patients undergoing ROB is markedly higher compared to controls. We report a mortality of 29% in the ROB group. Further, we found a correlation between ROB and increased preoperative predicted risk, as previously reported21.

Increased postoperative lactate as well as perioperative major bleeding have been shown to increase the risk for acute kidney injury22,23. Early onset postoperative lactatemia, detected during CPB or shortly afterwards, has been identified mainly as type A lactic acidosis24,25—a marker of tissue hypoxia, which is associated with adverse events during the postoperative period including a higher need for perioperative mechanical support, longer ICU stay, longer time of mechanical ventilation26, and significantly higher postoperative mortality27. Perioperative lactatemia, interpreted as an indicator of poor tissue perfusion, could further explain excessive fluid supply in this group of patients. Ranucci et al. have attributed tissue hypoxia during CPB to insufficient pump flow and hemodilution leading to reduced oxygen delivery (DO2)26. Thus, we can assume that excessive volume resuscitation during cardiac surgery may attenuate this effect. In addition, longer CPB time potentiates systemic inflammation28, leading to vasoplegia and potentially also threatening the integrity of the endothelial glycocalyx, causing causing interstitial fluid shifts29. Both factors may contribute to relative hypovolemia and edema, increasing oxygen diffusion distance, and worsening tissue hypoxia. In our study, various perioperative variables underline the evident risk for bleeding and acute kidney injury in the ROB group. In addition to higher EuroSCORE II values, increased lactate and base excess levels were observed preoperatively. Moreover, aortic cross-clamp time was prolonged in ROB patients. Postoperatively, hemoglobin and fibrinogen were decreased while creatinine, lactate, INR, and aPTT were significantly higher in ROB patients. Relative hypovolemia and lactatemia may have triggered the decision for increased volume substitution in the ROB group.

Concerning the perioperative administration of vasoactive agents, significantly higher cumulative doses of vasopressors were received by ROB patients. This might reflect the fact that higher doses were administered to patients with more serious bleeding. Furthermore, it must be pointed out that the cumulative dose of perioperatively administered epinephrine and norepinephrine was strikingly higher (threefold) when compared to the control. The advantage of the combined inotropic and vasoactive effect of epinephrine in the treatment of postoperative “myocardial dysfunction”30 and vasoplegia following a slightly longer CPB time in this group is a probable explanation. More importantly, this might be connected to higher blood loss, as higher doses of catecholamines favor coagulation. However, exogenous epinephrine attenuates the effect of perioperative catecholamine release causing insulin resistance, hyperglycemia, and lactate formation, which leads to type B lactic acidosis26,31. Type B lactic acidosis dominates the second peak of lactate levels, which typically occurs between 4 to 12 h postoperatively. This condition is known as late-onset lactatemia and has been described in 14–20% of patients undergoing elective and emergency cardiac surgeries. Interestingly, in-hospital mortality and probability of re-operation in these patients are similar when compared to patients with normal lactate levels32.

In an STS database analysis of 22 240 patients, a liberal postoperative fluid resuscitation protocol (> 5 RBC concentrates +  > 4 non-RBC products) without consecutive ROB resulted in a 30-day mortality of 20%21. Interestingly, mortality (19%) was comparable in patients who underwent liberal fluid treatment with consecutive ROB. However, mortality was significantly lower (6%) when patients underwent ROB without prior excessive fluid management. Although, these data do not explain whether the fluid protocol influenced the incidence of ROB, a plausible conclusion may be that ROB should not be delayed by liberal fluid management as it might increase the risk of mortality. In addition, recent data have shown the time of reoperation to be critical and to influence mortality. Mortality is as low 3.1% during the first four postoperative hours and is highest (43.8%) 25 to 48 h postoperatively. In addition, Pasrija et al. reported that reoperation within 24 h reduced the incidence of renal failure, length of hospital stay, and 30-day mortality21. In our study, by calculating the post-test probability, the highest AUROCs were shown between 5 and 7 h for fluid intake, fluid balance, blood loss, and norepinephrine. Although post-test probability was low for all of these variables, the trend correlates with existing literature. Future studies will tell if the low post-test probability observed in our study is reproducible in an elective patient cohort.

The influence of fluid resuscitation has been a focus of surgical research over the last two decades, but the debate about liberal vs. restrictive perioperative fluid regimens in major surgery is still ongoing. In a prospective randomized trial, restrictive fluid management reduced the rate of cardiopulmonary and wound complications after major colorectal surgery33. In a meta-analysis of 18 studies (5567 patients), no differences in terms of mortality and postoperative complications were discovered between liberal vs. restrictive fluid resuscitation after major abdominal surgery. Of note, in a subgroup analysis patients undergoing liberal resuscitation protocols presented with fewer renal complications34. The comparability of regimens in abdominal and cardiac surgery is questionable. Nevertheless, even if the main outcome variable is not usually bleeding in major abdominal surgery, the incidence of bleeding complications is similar to cardiac surgery and has been shown to be decreased by restrictive fluid management33,35. Although fluid demand is significantly higher in patients after cardiac surgery36, pioneering literature about fluid resuscitation in this patient group is scarce. While fluid regimens might vary between centers, postoperative outcomes are similar overall due to standardized procedures37,38. In our high-risk emergency CABG cohort, the change of fluid resuscitation protocol had no impact on the incidence of ROB. Although fluid intake, fluid balance, norepinephrine demand, blood loss, and VISmax were significantly higher in patients undergoing ROB, these outcomes did not allow a reasonable clinical transfer as predictive values.

Pre- and intraoperative patient characteristics have been repeatedly shown to be worse in patients at risk for postoperative ROB after cardiac surgery39. These patients are significantly older, have higher rates of heart and renal failure, have higher EuroSCORE II and preoperative aPTT values, and have lower hemoglobin levels than patients who did not undergo ROB21. In addition, emergency surgery and prolonged aortic cross-clamp time are independent risk factors for ROB39. The kidney is the organ most affected in critically ill patients. Fluid overload as a consequence of perioperative liberal fluid management may explain why the incidence of renal dysfunction was higher in patients undergoing ROB. Renal impairment may further augment perioperative metabolic acidosis. All of these mechanisms might trigger additional unnecessary fluid administration. Our data on eCABG patients partly confirm previous literature. While preoperative creatinine was comparable, the ROB group underwent surgery with higher EuroSCORE II and lactate as well as lower bicarbonate levels compared to controls. Postoperatively, bicarbonate, fibrinogen, hemoglobin, lactate, platelets, and fibrinogen were markedly reduced, and negative base excess, aPTT, and creatinine were increased. These results explain the higher rate of postoperative administration of blood products in the ROB group.

Study limitations

Limitations of this study are the retrospective design, the small number of patients who underwent ROB, and the differences in baseline characteristics. Authors interpret the slightly higher odds of re-operation after 2017 as the result of confounding factors and chance. As the change of management did not take place at a specific time point, patients were treated according to the changes to the fluid management algorithm that already occurred before 201840. As the cohort is rather small, the few high-risk patients might have large impact.

Appropriate fluid management remains a challenge not only in cardiac surgery. Although goal-directed hemodynamic therapy may be a beneficial strategy in terms of morbidity and length of hospital stay, it may also potentiate perioperative fluid administration and its adverse effects. Fluid responsiveness, defined as optimization of heterogeneous hemodynamic or metabolic parameters, should not always be interpreted as clinical hypovolemia. The uncertainty about the undeceiving parameters for guiding fluid resuscitation aimed at avoiding the consequences of fluid overload underline the importance of further research in this field.

To our knowledge, this is the first study to focus on volume resuscitation management and ROB after emergency CABG and in general cardiac surgery over time. In accordance with the aims of our study, fluid management does not appear to influence the incidence of ROB, and surgical revision remains the gold standard for management of excessive postoperative bleeding.

Supplementary Information

Supplementary Tables.

Abbreviations

ACT Activated clotting time

ALAT Alanine aminotransferase

aPTT Activated thromboplastin time

AUROC Area under the receiver operating characteristics curve

BIMA Bilateral internal mammary artery

BMI Body mass index

CABG Coronary artery bypass grafting

CAD 3 Three-vessel coronary artery disease

COPD  Chronic obstructive pulmonary disease

CPB Cardiopulmonary bypass

CVP Central venous pressure

DO2 Oxygen delivery

ECMO Extracorporeal membrane oxygenation

eCABG Emergency coronary artery bypass grafting

FFP Fresh frozen plasma

GCS Glasgow coma scale

IABP Intraaortic balloon pump

ICU Intensive care unit

INR International normalized ratio

LIMA Left internal mammary artery

MACCE Major adverse cardiac and cerebrovascular events

MAP Median arterial pressure

MI Myocardial infarction

NYHA New York Heart Association

OPCABG Off-pump coronary artery bypass grafting

PCI Percutaneous coronary intervention

RBC Red blood cell

RIMA Right internal mammary artery

ROB Reoperation for bleeding

VIS Vasoactive-inotropic score

VISmax Maximum vasoactive-inotropic score

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-71028-8.

Acknowledgements

We thank Allison Dwileski, MSc for editorial support and Klaus Baumgartl, Services for Analyse & Forschung, IT & Digitalisierung, University Hospital Basel for providing laboratory data.

Author contributions

The authors have contributed to this study, its conductance and publication of study results as follows: Substantial contributions to the conception or design of the work: Alexa Hollinger (A.H.), David Santer (D.S.), Martin Siegemund (M.S.); Statistics: Brigitta Gahl (B.G.); Planning, conduct and reporting of the work: Jowita Bruno (J.B.), Mascha Varayath (M.V.), A.H., and D.S.; Drafting the manuscript: J.B., M.V., A.H., D.S., and M.S.; Critical revision of the article and approval of the version published: all authors. Whenever possible, informed consent for emergency surgery was obtained from all subjects involved in the study. In 2017, the University Hospital Basel introduced a general consent procedure allowing researchers to use data obtained from patients during their hospital stay. Authors declared to the Ethics Committee of Northwestern and Central Switzerland that no data will be used in cases of documented decline to do so.

Data availability

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

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study has been approved by the Ethics Committee of Northwestern and Central Switzerland (Project-ID: 2020-01833) and was conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all national legal and regulatory requirements. The trial was registered at ClinicalTrials.gov (www.clinicaltrials.gov, identifier: NCT04533698) in August 2020.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Jowita Bruno, Mascha Varayath, Alexa Hollinger and David Santer.
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