Abstract
BACKGROUND:
Patients undergoing cardiac surgery often experience bleeding during and after the procedure. Antioxidants such as Vitamin C (VC) are used to manage postoperative bleeding and inflammation after cardiac surgery.
METHODS:
A total of 110 patients undergoing elective coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) were enrolled. Patients were randomly assigned into two groups of 55 participants each. In the intervention group, 25 mg/kg of VC was added to the CPB priming solution. In the control group, 25 mg/kg of normal saline was added instead. Nurse recorded the amount of chest tube drainage on intensive care unit (ICU) entry, and 2, 4, 6, 12, and 24 hours. They also documented the amount of blood product transfusion required during surgery and in the ICU.
RESULTS:
The amount of chest tube drainage in the control group was higher than the intervention group, but this difference was not statistically significant between the two groups (P > 0.05). The amount transfused blood in the operating room and in the ICU in the intervention group was 1.64±0.79 and 2.14±1.17 ml, respectively, and in the control group it was 1.69±0.84 and 2.52±1.68 ml, which was not statistically significant between the two groups (P > 0.05). There was no significant difference in duration of ICU and hospital stay between the two groups (P > 0.05).
CONCLUSION:
Adding VC to the CPB prime showed a non-significant trend toward reduced postoperative bleeding after CABG. Current evidence from this study is insufficient to recommend routine use; further larger trials are needed.
Key Words: Vitamin C; Coronary Artery Bypass Grafting; Prime Solution; Bleeding; Cardiopulmonary Bypass
Introduction
Patients undergoing cardiac surgery often experience bleeding during and after the procedure1,2. Reports indicate that postoperative bleeding occurs in about 25% to 50% of cases after coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB)1. As a result, patients undergoing cardiac surgery usually require more allogeneic blood transfusions than other surgical procedures3. However, the use of blood products is associated with several adverse outcomes, including the risk of infectious and viral diseases, immunosuppression, increased mortality, and prolonged hospitalization1,3.
One of the primary causes of bleeding during cardiac surgery is the use of CPB. The priming volume of the bypass circuit leads to hemodilution, and the contact of blood with the internal surfaces of the CPB machine induces mechanical damage to blood cells, disrupts platelet function, and disrupts coagulation mechanisms1. These effects contribute to reduced hemoglobin levels, impaired thrombin generation, converted fibrin formation, quantitative or qualitative platelet defects, and hyperfibrinolysis2,3.
In addition, postoperative bleeding may also be due to coagulation factor and platelet deficiency, incomplete reversal of heparinization, and increased fibrinolytic activity1. Despite these concerns, there is currently no universally accepted definition of intraoperative bleeding in cardiac surgery2. Nevertheless, the range of bleeding can be assessed by the requirement of the amount of chest tube drainage and the transaction of blood products4.
Previous studies have demonstrated that the use of CPB during cardiac surgery reduces plasma vitamin C (VC) during and after surgery1,5, decreasing by approximately 70% by 24 hours after surgery and may remain low for up to 2 weeks6. VC is a water-soluble vitamin that is not stored in the body and hence it should be replenished regularly through dietary intake7.
Antioxidants such as VC are used to manage postoperative bleeding and inflammation after cardiac surgery. VC plays an important role in strengthening immune function, collagen synthesis, iron absorption, anemia management and capillary walls1. It also contributes to hemostasis to promote platelet aggregation and prevent platelet disintegration, which reduces bleeding. Additionally, the first dose of VC can facilitate effective collagen cross-linking and capillary stability, potentially preventing bleeding within 24 hours8.
VC deficiency (below 0.2 mg/dL) has also been implicated in patients with heart disease in the pathogenesis of atherosclerosis and vascular stiffness1. Severe deficiency can lead to scurvy, which is a state of impaired collagen production and vascular delicate condition. The scurvy is associated with prolonged clotting time and delayed platelet aggregation, which highlights the important role of VC in the coagulation process9.
Given the inherent nature of cardiac surgery, the need for blood and blood product transfusions is often unavoidable. However, due to the limited availability of blood reserves, the high costs associated with transfusion, the reluctance of some patients to receive blood products, and the potential for transfusion-related complications1, efforts to reduce intraoperative and postoperative bleeding and thereby reduce transfusion requirements are of critical clinical importance.
Only a limited number of studies have examined the effects of VC on bleeding and blood product transfusion during cardiac surgery1,10,11. In these investigations, VC has been administered by various routes, including intravenous1,10, oral10, and cardioplegic solution delivery11. However, to date, no studies have specifically evaluated the effects of VC when included in the prime solution used during CPB.
Accordingly, the present study was conducted to investigate the effect of adding VC to the CPB prime solution on postoperative bleeding and the requirement for blood product transfusions in patients CABG.
Materials and Methods
The study was designed as a random, triple-blind, single-center, controlled clinical trial held between 2024 and 2025. This trial was conducted in accordance with the Declaration of Helsinki and was approved by the Research Ethics Committee of Isfahan University of Medical Sciences (Code: IR.MUI.MED.REC.1403.193) and registered with the Iranian Registry of Clinical Trials (Trial Code: IRCT20200825048515N75).
With a 95% confidence level and 80% power, considering the standard deviation of drainage volume 2 hours after surgery in the tranexamic acid and tranexamic acid + Vitamin C groups in previous studies1 equal to 20 and 15, respectively and the error level obtained from the mean of two groups equal to 0.8, the sample size of 55 patients was considered for each group. A total of 110 patients undergoing elective CABG with CPB were enrolled. Inclusion criteria included age over 35 years and EF over 30%. Exclusion criteria included undergoing concurrent cardiac surgeries along with CABG, history of VC use in the last three months, history of corticosteroid use before hospitalization, redo surgery, drug reaction and any problems during surgery and anesthesia, use of intra-aortic balloon pump or extracorporeal membrane oxygenation (ECMO), and history of celiac disease (due to its effect on VC levels) or malabsorption problems.
Prior to enrollment, all patients were provided with detailed information about the study protocol, and written informed consent was obtained. Participants who withdrew consent at any point were excluded from the study.
Then using random allocation software, these patients were divided into two groups of 55 (Fig. 1). In the intervention group, 25 mg/kg of VC was added to the CPB priming solution. In the control group, 25 mg/kg of normal saline was added instead12. The standard priming solution consisted of 1000 cc of Ringer’s lactate, 500 cc of Voluven, and 10,000 units of heparin.
Figure 1.
CONSORT flowchart showing the number of patients at each phase of the study.
In order to achieve a triple-blind study, both VC and placebo solutions were pre-prepared and labeled as “A” and “B” by the principal investigator. The perfusionist, blinded to the group allocation, added the assigned solution to the priming fluid and collected the necessary intraoperative data. intensive care unit (ICU) nurses, patients, and the data analyst were all blinded to group assignments.
Demographic information was collected preoperatively. All patients underwent standard ASA monitoring, and arterial and central venous lines (CVC) were placed. General anesthesia was induced according to the hospital’s standard protocol, followed by CABG with CPB. Intraoperatively, all administered blood products were recorded.
After surgery, patients were transferred to ICU. ICU nurses recorded the amount of chest tube drainage on ICU entry, and 2, 4, 6, 12, and 24 hours1. They also documented the amount of blood product transfusion required during the ICU stay.
Statistical Analysis
Finally, the collected data was entered into SPSS (version 27; SPSS Inc., Chicago, Ill., USA) and was represented by frequency (percent), Mean ± SD or Median [IQR]. To compare the mean or frequency distribution of the patients’ baseline characteristics between the two groups, independent sample t-test and Chi-square were used, respectively. Also, according to the result of the Kolmogorov-Smirnov test indicating the abnormality of data distribution, the Mann-Whitney test was used to compare quantitative variables (chest tube drainage or amount of blood product transfusion) between the two groups, and the Friedman test was used to compare the trend of mean changes over time. Also, the frequency percentage of blood product needs was compared between the two groups with Fisher’s exact test. In all analyses, a significance level of less than 0.05 was considered.
Results
In the present study, the intervention group included 15 (27.3%) female and 40 (72.7%) male with a mean age of 62.44±7.04 years, and the control group included 15 (27.3%) women and 40 (72.7%) men with a mean age of 60.44±7.81 years. The two groups were similar in terms of basic and clinical characteristics (P > 0.05) (Table 1).
Table 1.
Comparison of the patients’ basic and clinical characteristics between two groups
| Characteristics | Intervention Group (n = 55) | Control Group (n = 55) | P-value | |
|---|---|---|---|---|
| Gender | Female | 15(27.3%) | 15(27.3%) | >0.99* |
| Male | 40(72.7%) | 40(72.7%) | ||
| Age (years) | 62.44±7.04 | 60.44±7.81 | 0.161** | |
| Weight (kg) | 73.20±10.28 | 74.24±14.89 | 0.672** | |
| Comorbidities | Diabetes | 23(41.8%) | 18(32.7%) | 0.430* |
| Hypertension | 22(40.0%) | 27(49.1%) | 0.443* | |
| Hyperlipidemia | 30(54.5%) | 28(50.9%) | 0.849* | |
| Other | 1(1.8%) | 1(1.8%) | 1.00* | |
| Number of Grafts | 2 grafts | 7(12.7%) | 6(10.9%) | 0.949* |
| 3 grafts | 30(54.5%) | 30(54.5%) | ||
| 4 grafts | 18(32.7%) | 19(34.5%) | ||
| Aortic Clamp Time (min) | 57.43±16.07 | 57.01±15.43 | 0.890** | |
| Total Cardiac Arrest Time (min) | 59.32±16.47 | 59.78±16.43 | 0.885** | |
*: The significance level obtained from the independent t-test to compare the means of quantitative variables between the two study groups. **: The significance level obtained from the chi-square test to compare the frequency distribution of qualitative variables between the two study groups.
The amount of chest tube drainage in the control group was higher than that in the intervention group at all follow-up times after surgery, although this difference was not statistically significant (P > 0.05). In contrast, in each of the two groups, the amount of chest tube drainage increased significantly during the first 24 hours after surgery (P < 0.001) (Table 2).
Table 2.
Comparison of the mean amount of chest tube drainage between two groups
| Amount of Chest tube drainage (ml) | Intervention Group (n = 55) | Control Group (n = 55) | P value1 |
|---|---|---|---|
| After admission to the ICU | 19.09±49.52 0[0-100] | 28.18±62.92 0[0-100] | 0.679 |
| 2 hours after surgery | 86.36±109.05 50[0-100] | 108.18±114.56 100[0-150] | 0.177 |
| 4 hours after surgery | 59.09±133.71 0[0-100] | 70.90±121.97 0[0-100] | 0.525 |
| 6 hours after surgery | 85.45±137.99 50[0-100] | 95.45±106.40 50[0-150] | 0.326 |
| 12 hours after surgery | 105.45±139.00 100[0-150] | 110.90±122.73 100[0-150] | 0.609 |
| 24 hours after surgery | 95.45±95.39 100[0-150] | 130.90±136.24 100[0-150] | 0.206 |
| P value2 | <0.001 | <0.001 |
Data presented as mean ± standard deviation(SD) and median [IQR]. 1-The significance level obtained from the Mann-Whitney test comparing the variable mean rank between two groups at each time 2- The significance level obtained from the Friedman test for comparing the variable mean rank over time in each of the two groups
The results of comparing amount transfused blood and blood product transfusion in the operating room and in the ICU between the two groups showed that the frequency of blood and platelet transfusion in the operating room was higher than in the ICU, and the lowest percentage of fresh frozen plasma (FFP) transfusion was reported. The amount transfused blood in the operating room and in the ICU in the intervention group was 1.64±0.79 and 2.14±1.17 ml, respectively, and in the control group it was 1.69±0.84 and 2.52±1.68 ml, which was not statistically significant between the two groups (P > 0.05). Also, the mean amount of platelets and FFP in the operating room and in the ICU were not significantly different between the two groups (P > 0.05) (Table 3).
Table 3.
Comparison of the amount transfused blood and blood product transfusions between two groups
| Variables | Intervention Group (n = 55) | Control Group (n = 55) | P value1 | |
|---|---|---|---|---|
| Blood Transfusion | ||||
| In operating room | Transfusion | 42(76.4%) | 45(81.8%) | 0.794 |
| Amount transfused | 1.64±0.79 1.00[1.00-2.00] | 1.69±0.84 1.00[1.00-2.00] | ||
| In ICU | Transfusion | 44(80.0%) | 47(85.5%) | 0.176 |
| Amount transfused | 2.14±1.17 2.00[1.00-2.00] | 2.52±1.68 2.00[1.00-3.00] | ||
| Platelet Transfusion | ||||
| In operating room | Transfusion | 35(63.6%) | 45(72.7%) | 0.496 |
| Amount transfused | 4.20±1.78 5.00[1.00-5.00] | 3.92±1.70 5.00[1.00-5.00] | ||
| In ICU | Transfusion | 13(23.6%) | 13(23.6%) | 0.296 |
| Amount transfused | 4.69±1.11 5.00[1.00-5.00] | 4.08±1.75 5.00[1.00-5.00] | ||
| FFP Transfusion | ||||
| In operating room | Transfusion | 2(3.6%) | 2 (3.6%) | 0.875 |
| Amount transfused | 3.50±1.00 3.00[1.00-2.00] | 5.00±1.00 5.50[1.00-2.00] | ||
| In ICU | Transfusion | 6(10.9%) | 12(21.8%) | 0.749 |
| Amount transfused | 4.50±2.34 5.00[1.00-5.00] | 4.25±0.96 4.00[1.00-5.00] | ||
Data presented as mean ± standard deviation (SD) and median [IQR]. 1- The significance level obtained from the Mann-Whitney test comparing the variable mean between two groups at each time
Finally, according to Table 4, no postoperative complications (including atrial fibrillation (AF), stroke, and sternal wound infection) were reported, and only one patient (1.8%) died in the intervention group. There was no significant difference in the duration of ICU and hospital stay, and need for defibrillation after aortic unclamping between the two groups (P > 0.05).
Table 4.
Comparison of postoperative complications and outcomes between two groups
| Outcomes | Intervention Group (n = 55) | Control Group (n = 55) | P value |
|---|---|---|---|
| Length of ICU stay (days) | 2.75±0.72 | 2.65±0.61 | 0.480* |
| Length of hospital stay (days) | 4.09±1.25 | 4.22±1.44 | 0.623* |
| Need for defibrillation after aortic unclamping | 2(3.6%) | 4(7.3%) | 0.679** |
| Postoperative Complications | |||
| AF | 0(0.0%) | 0(0.0%) | - |
| Stroke | 0(0.0%) | 0(0.0%) | - |
| Sternal wound infection | 0(0.0%) | 0(0.0%) | - |
| Final Outcome | |||
| Alive | 54(98.2%) | 55(100.0%) | >0.99** |
| Deceased | 1(1.8%) | 0(0.0%) | |
Data presented as frequency (percentage) or mean ± standard deviation(SD). *: The significance level obtained from the independent sample t-test comparing the variable mean between two groups **: The significance level obtained from the Fisher exact test comparing the frequency percentage of variable between two groups
Despite substantial advances in cardiac surgery, the management of perioperative bleeding remains a major clinical challenge. Cardiac surgery remains a high risk of bleeding, and intraoperative blood loss is often managed using allogeneic blood products, making it one of the surgical procedures with the highest transfusion rates2. This randomized clinical trial aimed to evaluate the effect of adding VC to the CPB prime solution on postoperative bleeding and transfusion requirements in patients undergoing CABG.
The results demonstrated that chest tube drainage in both groups was minimal upon admission to the ICU, increased between 2 and 12 hours postoperatively, and subsequently decreased within 24 hours after surgery. Although the mean drainage volume was consistently lower in the VC group compared with the control group, the difference did not reach statistical significance. Nonetheless, this finding suggests a potential hemostatic benefit from the addition of VC to the prime solution.
Blood transfusions occurred more frequently in the ICU than in the operating room for both groups. Platelet transfusions occurred predominantly intraoperatively, while FFP administration was relatively low overall. The mean volume of blood and blood product transfusion was lower in the VC group, especially in the ICU, although this reduction was not statistically significant. From a clinical perspective, even small reduction in transfused blood units can have a positive impact on patient outcomes and reduce healthcare costs.
To date, few studies have explored the effects of VC on postoperative bleeding in cardiac surgery, and most have not determined the exact amount of postoperative blood loss. Ghorbaninezhad et al.1 compared tranexamic acid alone with tranexamic acid combined with VC in CABG patients and found that the combination reduced bleeding without affecting the incidence of AF. Similarly, Sadeghpour et al.10 administered intravenous VC before surgery followed by oral supplementation for four days postoperatively, reporting reductions in ICU mortality, hospital length of stay, postoperative drainage, and intubation time. Jalili Shahandashti et al.11 added VC to the cardioplegic solution during CABG and a lower rate of FFP transfusion was observed in the ICU; however, no significant differences were found in blood or platelet transfusion frequencies between the groups.
Other researchers have investigated the hemostatic effects of VC in non-cardiac surgeries, with variable results. Significant reductions in blood loss were reported during large colorectal polypectomy7 and total abdominal hysterectomy8, whereas no association was observed in laparoscopic myomectomy13, a finding likely due to the less bleeding of minimally invasive surgery. In a systematic review and meta-analysis, Abu-Zaid et al.9 reported no significant difference in intraoperative blood loss between groups, but there was less need for blood product transfusions among patients receiving VC.
Although the physiological mechanisms of VC are similar in all surgical contexts, the pathophysiological conditions differ markedly between cardiac and non-cardiac surgery. Cardiac procedures associated with CPB expose blood to non-endothelial surfaces, triggering a strong systemic inflammatory response, hemodilution, hypothermia, and both quantitative and qualitative platelet dysfunction. Additional factors, including heparin administration and its reversal with protamine, CPB duration, and aortic cross-clamp time, further influence the risk of bleeding3. Therefore, findings from non-cardiac surgeries cannot be directly extrapolated to cardiac operations.
VC is a reversible reducing agent and an essential electron donor in many biochemical and enzymatic reactions. It plays an important roles in collagen synthesis, neurotransmitter production, nitric oxide synthesis, and fatty acid metabolism14. VC exerts both enzymatic and non-enzymatic effects: enzymatically, it facilitates collagen cross-linking, enhancing capillary integrity and tissue repair; non-enzymatically, it acts as a potent intra- and extracellular antioxidant. During hemostasis, platelet aggregation and activation form the primary hemostatic plug, a process that depletes platelet VC levels. In the subsequent fibrin-clot phase, reactive oxygen species are generated, contributing to platelet damage. As a result, VC administration may reduce secondary or functional thrombocytopenia and increase platelet-fibrin clot stability, thereby reducing primary bleeding. Furthermore, VC acts as an important cofactor for lysyl and prolyl hydroxylase, two enzymes essential for collagen biosynthesis. VC deficiency results in unstable, poorly cross-linked collagen with low tensile strength and high susceptibility to enzymatic degradation. VC supplementation promotes effective collagen cross-linking within 24 hours, improves vascular integrity, and promotes hemostasis7. These biochemical mechanisms may underlie the reduction in surgical bleeding observed in previous studies.
In our study, no statistically significant differences were observed between the two groups regarding postoperative complications. Neither group experienced AF, stroke, or sternal wound infection, and only one patient died in the intervention group. Considering that chest tube drainage, as well as blood and blood product transfusions, were not increased in the intervention group, the administration of VC in the CPB prime solution appears safe, without adverse effects, and can be used reliably.
This study was conducted at a single center by the same surgeon and surgical team. Therefore, all surgery-related confounding factors, including CPB duration, aortic cross-clamp time, type of procedure, surgical technique and surgeon experience, body temperature during CPB, use of hemostatic medications, and the number and type of surgical drains, were consistent between groups. This uniformity represents a major strength of the study. However, due to some limitations, baseline VC levels were not measured in patients before the intervention. Furthermore, VC was administered only intraoperatively via the prime solution and was not continued postoperatively. Although the use of a single intraoperative dose may not maintain high plasma levels throughout the postoperative period, the focus of this study was to target the critical step of endothelial injury, oxidative stress during CPB.
The absence of meta-analyses evaluating the effect of VC on bleeding and transfusion requirements in cardiac surgery suggests that robust evidence for its efficacy remains limited. As a result, we recommend that future trials, in the form of multicenter studies with larger sample sizes investigate the role of VC in reducing bleeding and transfusion needs in cardiac surgery. Future studies should also evaluate combined intraoperative and postoperative regimens to determine the optimal dosing strategy.
Conclusion
According the results of this study, the administration of VC in the prime solution demonstrated a trend toward reduced bleeding after CABG; however, this effect was not significant. Thus, this purpose cannot be recommended based on the present findings. Also, no differences in postoperative complications were observed between the intervention and control groups. To strengthen the evidence regarding the role of VC in reducing bleeding and related complications during CABG surgery, further research is needed. In particular, larger-scale, randomized controlled trials are needed to provide more robust and generalizable findings.
Acknowledgements
The authors would like to thank the nursing staff and surgical team of the cardiac surgery department for their assistance in data collection and patient care during the study.
Conflict of interests
The authors declare no conflict of interest.
Funding
There is no funding in this study.
Author’s Contributions
Study Conception or Design: AH; MS; MM
Data Acquisition: AH; MM
Data Analysis or Interpretation: AMM
Manuscript Drafting: MS; MM
Critical Manuscript Revision: AH; AMM
All authors have approved the final manuscript and are responsible for all aspects of the work.
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