Heparin rebound in patients undergoing off-pump coronary artery bypass grafting surgery: a single-center retrospective study

Abstract

Background

Heparin, an anticoagulant used in cardiac surgery, can result in heparin rebound (HR), where it returns postoperatively despite being neutralized with protamine. This study was designed to investigate the prevalence of HR in patients undergoing off-pump coronary artery bypass grafting (OPCAB) and evaluate the impact of HR on their short-term outcomes.

Methods

HR was defined by a 10% increase in activated coagulation time (ACT) following two hours of heparin neutralization with protamine, bleeding over 200 mL/h, and abnormal laboratory coagulation examination results. We analyzed 503 OPCAB patients aged 31–80 years from September 2019 to June 2022, who were categorized into HR (n = 56) and Non-HR (n = 447) groups. The primary outcome was postoperative bleeding volume. Secondary outcomes included the incidence of postoperative reoperation for bleeding, allogenic blood transfusion incidences and volumes, and laboratory variables.

Results

Significant differences were observed in preoperative platelet counts (P < 0.001) and the ACT measured 2 h post-heparin neutralization (P = 0.012). The group HR exhibited higher 24-hour bleeding volumes, increased reoperation rates, and greater total bleeding volumes (all P < 0.001).

Conclusions

Postoperative HR was found to be prevalent in OPCAB patients and increased bleeding risks. These findings indicate the need for future randomized controlled trials to confirm the impact of HR and guide patient blood management.

Introduction

Heparin Rebound (HR) is a phenomenon where heparin’s anticoagulant effects re-emerge postoperatively after being neutralized with protamine during cardiac surgery [1]. HR may lead to increased bleeding following surgery, and in cases where prolonged coagulation times and/or continued bleeding are observed, additional doses of protamine may be required. Various definitions of HR can be found in the literature. For example, some groups considered a prolonged coagulation-based laboratory test, such as the activated coagulation time (ACT), activated partial thromboplastin time (APTT), prothrombin time (PT), or international normalized ratio (INR), as an indicator of HR [2,3,4,5,6]. In addition, some groups suggested both increased bleeding (at a rate of more than 200 mL/h) and abnormal laboratory test results for a diagnosis of HR [7]. Off-pump coronary artery bypass grafting (OPCAB) is widely recognized as a safe procedure for treating ischemic heart disease. Numerous research studies have consistently demonstrated that OPCAB results in fewer complications compared to on-pump coronary artery bypass graft (CABG) [8, 9]. However, the authors’ conclusions do not adequately consider the multifactorial complexity of postoperative bleeding. While the authors do acknowledge the potential occurrence of the HR phenomenon, which may contribute to abnormal bleeding, further exploration of this topic is necessary.

Therefore, additional research is needed to confirm these findings. Consequently, the present study aims to investigate the specific characteristics of HR associated with OPCAB.

Methods

Study design and population

Informed consent was not requested as this study is a retrospective chart review. The study did not involve the identification of patients’ personal information. Consecutive patients who underwent primary and isolated OPCAB at a large-volume cardiovascular center between September 2019 and June 2022 were screened for eligibility. The inclusion criteria are as follows: (1) adult patients (> 18 years old); (2) patients undergoing OPCAB; (3) normal preoperative coagulation function. Exclusion criteria include: (1) taking anticoagulant drugs; (2) emergency OPCAB; (3) patients with missing or incomplete outcomes of interest; (4) prior cardiac surgery.

Anesthetic and surgical protocol

Chronic cardiac medications, such as anti-hypertensive and anti-anginal agents, were continued up to the morning of surgery. Anti-platelet and anticoagulation medications were discontinued 8 days before surgery. No anesthetic premedication was given. For anesthesia induction, etomidate was administered at a dose of 2 mg kg ^− 1, sufentanil at a dose of 2–3 µg kg ^− 1, and cis-atracurium at a dose of 0.15–0.2 mg kg^− 1. For anesthesia maintenance, propofol was administered at a rate of 100–200 mg h ^− 1, dexmedetomidine at a rate of 30–50 µg h ^− 1, cis-atracurium at a rate of 10–20 mg h ^− 1, and sevoflurane at a concentration of 0.5-2.5%. No included patient in the current study received epidural anesthesia, spinal morphine, or erector spinae block. Aspirin alone or in combination with a P2Y12 inhibitor (clopidogrel or ticagrelor) was administered orally after the removal of the chest drainage tube in the postoperative period, as determined by the surgeons.

During the coronary graft procedure, all subjects underwent a sternotomy at the median, where the left internal thoracic artery and/or great saphenous veins were extracted. To ensure adequate clot formation, a heparin (Shanghai First Biochemical Pharmaceutical Co., Ltd., China, 2 ml: 12,500 u) dosage of 200 IU/kg was administered, which led to an ACT exceeding 300 s. Towards the end of the revascularization process, protamine (Beijing YueKang Kaiyue Pharmaceutical Co., Ltd., China, 5 ml: 50 mg), was used to counteract the effects of heparin at a ratio ranging from 0.8 to 1. Additional protamine sulfate was administered based on the ACT ( Medtronic ACT II analyzer, Medtronic Inc., USA). Additionally, all study participants received intraoperative autologous blood retrieval using cell saver systems.

Criteria for allogeneic transfusion and reoperation

Postoperative blood loss was assessed by measuring the total amount of fluid collected from the chest drainage tube starting from the end of the surgery until its removal. In order to determine the need for blood transfusion, A large-volume cardiovascular center Hospital followed a specific transfusion protocol. For example, if the hemoglobin level dropped below 8.0 g dl^− 1, a red blood cell (RBC) transfusion was initiated. Fresh frozen plasma (FFP) infusion was administered in cases of diffuse bleeding with prothrombin time 1.5 times longer than the baseline value. Platelet concentrate (PC) transfusion was deemed necessary if the platelet count fell below 50 × 10⁹/l or in instances of platelet (PLT) dysfunction. Reoperation was carried out if the volume of fluid collected from the chest tube exceeded 300 ml h^− 1 within the first 2 h or 200 ml h^− 1 for 4 h. The chest drainage tube was only removed when the rate of fluid discharge was less than 20 ml for a duration of 5 to 6 h.

Data collection

This gathered information encompasses baseline characteristics comprising age, weight, and height, along with coagulation-related laboratory tests, such as ACT, APTT, PT, PLT count, INR, and heparin sensitivity index (HSI), HSI=(ACT after initial heparin administration – ACT baseline)/initial heparin dose (seconds/(IU/kg)).

Data were gathered from hospital electronic medical records, encompassing laboratory test outcomes, perioperative status, and postoperative recuperation. Subsequent to the surgical procedure, the patient was moved to the Intensive Care Unit (ICU), where the nurse recorded the length of mechanical ventilation, chest tube drainage, and postoperative allogeneic blood transfusion.

Statistical analysis

For continuous variables with non-normalization distribution, median [IQR (lower quartile, upper quartile)] was presented. For continuous variables with normalization distribution, mean (SD) was presented. The normality of quantitative data was examined by the Shapiro–Wilk test. For comparison between groups, continuous and categorical variables were tested by t-test or the Mann–Whitney U test and Pearson’s χ2 or Fisher’s exact test, respectively. P < 0.05 was considered statistically significant. Missing data were treated as missing and omitted from analysis, and no replacement was applied. All statistics were performed using SPSS (version 27.0.1).

Results

The patient selection process is shown in Fig. 1. Totally, 503 patients were finally included and divided into group HR (n = 56) and group Non-HR (n = 447).

Patient characteristics, preoperative and intraoperative data of the study population were summarized in Tables 1 and 2. No significant differences were observed in patient characteristics such as gender, age, body weight, body mass index, smoking, and drinking habits, or blood types between the HR and Non-HR groups. No important differences in patient characteristics and intraoperative volume balance were found between the HR and Non-HR groups. There was no significant difference in preoperative APTT, PLT count, PT, INR, and HSI.

Fig. 1

Enrollment flowchart

Table 1 Preoperative variables

Table 2 Intraoperative variables

Postoperative variables of included patients were summarized in Table 3. At univariate analysis, there was difference with respect to preoperative PLT count (132.5(108.5-167.8))10⁹/l vs. (164.0(128.3–195.0))10⁹/l, P < 0.001. However, after full antagonism of protamine, during the ACT of 2 h post-heparin neutralization, a significant difference was identified between the two groups, and there was no notable difference in the total amount of protamine administered. There was a significant difference in the 24-hour bleeding volume (P = 0.000) and total bleeding volume (P < 0.001), revealing statistical significance between the two groups.

Table 3 Postoperative variables

Postoperative outcomes were summarized in Table 4. There was a significant difference in reoperation for bleeding (P < 0.01). However, there were no significant differences in mechanical ventilation duration, ICU length of stay, or hospital length of stay between the groups.

Table 4 Postoperative outcomes

Discussion

Our investigation aimed to explore heparin rebound (HR) in patients undergoing OPCAB, with a focus on the premature elimination of protamine and its implications for coagulation time and bleeding [10]. In a study conducted by Gravlee and colleagues, an analysis was carried out on variations in the levels of ACT in patients undergoing cardiac surgery at different time points [11]. Our findings, in accordance with previous research, identify HR as a contributing factor to postoperative bleeding following cardiac surgery [12]. Notably, the significant difference in ACT values 2 h post-neutralization between groups emphasizes the necessity of comprehending the temporal dynamics of HR in OPCAB [13]. This understanding is crucial for optimizing patient outcomes and minimizing bleeding complications. We suggest increasing the protamine dosage to minimize the incidence of HR, acknowledging that factors other than HR, such as thrombocytopenia and coagulation factor insufficiency, may elevate ACT [14]. The anticoagulant mechanism of heparin involves binding with Antithrombin III (AT-III), forming a complex that deactivates thrombin on the platelet membrane [15,16,17,18]. The efficacy of heparin depends on AT-III, highlighting its role in HR management [19]. Our study reveals postoperative platelet count differences, suggesting that monitoring coagulation function can preliminarily indicate the occurrence of HR. Increasing the protamine dosage can reduce 24-hour postoperative bleeding [20]. The sensitivity of APTT to coagulation factor deficiency and heparin indicates that 82% of samples show factor deficiencies or other inhibitors, rather than being related to heparin [20]. An increase in PT-INR occurs with defects in factors II, VII, and X, but normal PT-INR requires sufficient levels of factors V, thrombin, and fibrin. Thus, PT-INR alone is not suitable for detecting heparin activity. Carr et al. found that reversing heparin-induced platelet dysfunction requires a higher protamine dose than normalizing APTT, suggesting that the antiplatelet effect of high-dose heparin may persist despite APTT correction [21]. The influence of heparin rebound on postoperative bleeding seems to be negligible, but might get significant in conjunction with incomplete heparin reversal or other coagulopathies [22]. Therefore, it may be useful to obtain images of the complete coagulation spectrum after cardiac surgery, which could be achieved by a combination of viscoelastic and aggregation testing [22].

There were some limitations worth to be mentioned. Firstly, it was a single-center retrospective study which might have patient selection bias. Secondly, although we estimated the sample size, it might still be insufficient due to heterogeneity resulted from different anesthesiologists, surgeons, and patients. Future research should concentrate on predictive models for HR and personalized anticoagulation techniques, as well as the influence of protamine administration schedules on HR and the role of novel anticoagulants in cardiac surgery.

Conclusions

HR and incomplete heparin reversal are commonly observed after cardiac surgery with OPCAB, and these phenomena may contribute to an increased risk of postoperative bleeding. To mitigate this risk, it is important to predict the likelihood of heparin rebound in patients by monitoring postoperative platelet count and the ACT values measured 2 h after the administration of the neutralized dose. By implementing appropriate measures, such as timely intervention, it is possible to prevent postoperative bleeding and the need for reoperation due to bleeding.