Postoperative atrial fibrillation (POAF) is an increasingly recognized common complication following coronary artery bypass grafting (CABG) surgeries ¹. POAF has implicated in various clinical and financial burdens. These include increased stroke risk, the need for additional anticoagulant treatment and increased susceptibility to nosocomial infections. Consequently, all of these will end up extending the overall duration of hospital stay. Although POAF is a common type of atrial fibrillation (AF) occurring after cardiac surgeries, its exact definition is still not fully understood. For instance, some researchers and physicians define it as AF occurring within 4 weeks after cardiac surgeries without prior history of AF ². On the other hand, others have defined it as AF episodes lasting more than 30 seconds or persisting for more than 10 minutes following cardiac operation despite electrolyte deficit correction that need electrical or pharmacological cardioversion using antiarrhythmic drug during the hospital stay ³ . Several clinical and demographic factors have been found the cause of increasing the likelihood of patients experiencing POAF occurrence. These include extent of heart dysfunction, a history of myocardial infarction (MI), diabetes, hypertension, hyperlipidemia, patient’s age, previous AF episodes, and valvular disease.

Even after implementing all the recommended prophylactic measures, such as beta-blockers and statins, physicians still face the challenge of a high rate of POAF occurrence. ^4,5. Numerous clinical and experimental investigations indicate that the inflammation and oxidative stress induced by ischemia/reperfusion events during CABG surgery are the main causes of electrical alterations in the atrium resulting in POAF occurrence ⁶ . Based on these hypotheses, researchers have investigated the potential of utilizing vitamin C as an antioxidant in minimizing oxidative stress induced by CABG surgeries, leading to reducing the incidence of POAF ^7,8 . Moreover, vitamin C plays a vital role in collagen biosynthesis, L-carnitine production, and specific neurotransmitters synthesis. Additionally, vitamin C has been observed to stimulate the production of other antioxidants in the body including α-tocopherol (vitamin E) ^9,10 .

The efficacy of using relative doses of vitamin C as an adjunctive medication to beta blockers and statins for POAF prevention remains an area of debate ^11,12 . Therefore, this study aimed at evaluating the efficacy of oral vitamin C as an adjunctive therapy for the prevention of POAF as well as determining the most effective dose regimen. Indeed, the protective effect of vitamin C against POAF has been studied in terms of ventilation time and the duration of hospitalization in the Intensive Care Unit.

Patients

Patient Population

Patients subjected to CABG surgeries in the Cardio-thoracic Department at El-Sheikh Zayed specialized hospital, Giza, Egypt, from January 2021 to January 2023 were screened for the eligibility criteria. Patients were screened after full history taking, physical examination and complete investigations including ECHO. Patients included in this study administered medications for the prevention of atrial fibrillation as per the suggested protocol established by clinical pharmacist in accordance with international guidelines and endorsed by the Cardiothoracic surgery department. All the participated candidates were given a detailed description for the informed consent to ensure that they understood all the information before obtaining their informed consents.

The study protocol was approved by the Research and Ethics Committee of the Faculty of Pharmacy, Helwan University, and the Hospital Medical Ethical Committee which followed the tents of declaration of Helsinki and the Guidelines for Good Clinical Practice, with approval code: 03H2020. An approval was also obtained from clinical trail.gov with a registration number: NCT06074367.

Inclusion Criteria

Patients with coronary artery disease, who are candidates for CABG surgeries, were selected according to the following criteria: a) Elective isolated on-pump CABG surgery with full sternotomy and mild hypothermia (34° C)., b) Age ranged from 50 to 70 years, c) No history of CABG surgery, d) Taking maximum tolerated beta-blocker, statin dose before and after surgery, e) Normal left atrium and left ventricle dimensions.

Exclusion Criteria

Patients who met one or more of the following criteria have been excluded from the study: a) Patients who need emergent CABG surgery, b) Preoperative history of AF or permanent pacemaker or significant bradycardia c) History of amiodarone use, d) Left ventricular ejection fraction < 40%, e) Those who have any contraindications to b-blocker, statin or vitamin C, f) Patients with chronic liver or kidney diseases, g) Patients underwent off-pump surgery, h) Patients with history of vitamin C supplementation at least 1 week before surgery, i) Patients failed to sign an informed consent.

Methods

Study Design

This study was a randomized, prospective, double blinded, placebo-controlled interventional study; both participant (patients) and care providers (nurses, cardiac surgeons, and ICU physicians) were blinded. All groups were operated by the same surgical team and received similar preoperative and postoperative ICU care.

Methodology

The study population was randomized 2 days before conducting the surgery into 3 groups using randomizer website (ref:www.randomaizer.org). The method of randomization depended on random allocation sequence generated with a computer random number generator. The 3 randomized groups were as follows:

High dose group (Gp HD); CABG patients who received maximum tolerated dose of b-blocker, statins & C-Retard 500 mg capsules (2 gm daily divided into 4 divided doses). On the other hand, Low dose group (Gp LD); CABG patients who received maximum tolerated dose of b-blocker, statins, C-Retard 500 mg capsules (1 gm daily divided into 2 doses) in addition to 2 starch capsules to be completely equivalent in dose administration frequency to the other groups.

Placebo group (GpP); CABG patients who received maximum tolerated dose of b-blocker, statins and placebo starch capsules mimicking C-Retard capsules every 6 hrs. The placebo capsules were prepared in the similar shape and size to

those of the C-retard capsules. Vitamin C was provided to patients in the form of C-Retard® , 500mg capsules, Hikma, Egypt.

Follow up

All groups started receiving their intervention one day before operation till the end of hospital stay or development of POAF. In addition, they have also received the same preoperative medical premedication according to the approved hospital protocol and underwent the same intraoperative protocol.

Data Collection

Patients’ demographics such as age, gender, and concurrent health conditions e.g. diabetes mellitus, hypertension, dyslipidemia, history of AF, as well as the presence of any liver or kidney diseases were collected. Preoperative angiography, echocardiography and electrocardiograms (ECGs) were carried out. Responses such as cardio-pulmonary bypass time (CPB), aortic cross-clamp time, and grafts number were monitored and recorded intra-operatively. Parameters such as ventilation time, length of ICU stay, and administration of inotropic agents within the initial 24 hours in ICU care were monitored regularly. Additionally, any occurrence of POAF within the ICU was recorded. Generally, Holter was placed for monitoring of AF for patients during hospitalization and total hospital stay.

Statistical analysis and sample size collection

The sample size calculation was done assuming 24% as an absolute difference between different groups as proved by previous studies ¹³ . Atrial fibrillation was assumed to occur in approximately 32% and 8% of patients undergoing coronary artery bypass grafting surgeries without and with vitamin C administration, respectively. Therefore, 43 patients were required in each group to attain a statistically significant α score of 0.05 and power of 80%. G*Power 3.1.9.7 software was used for sample size calculation utilizing Z tests for detecting the difference between two independent proportions. Therefore, 60 subjects were selected for each study group in order to compensate any losses that may occur within the patient groups due to missing one or more of their eligibility criteria during the study.

Statistical analysis was carried out using IBM SPSS® Statistics version 26 (IBM® Corp., Armonk, NY, USA). Numerical data are presented as mean ± standard deviation or median and range as appropriate. Qualitative data are presented as frequency and percentage. Relations between qualitative variables were evaluated using Pearson’s Chi- square test. Analysis of variance (ANOVA) was used for normally distributed quantitative data for comparing between the three studied groups. On the other hand, non-normally distributed data were evaluated using Kruskal-Wallis test (non- parametric ANOVA) followed by post-Hoc test" for pair-wise comparison. All tests were two-tailed, Where a p-value <

0.05 was considered significant.

3.1.  Patient enrollment and pretreatment clinical data

Eligible patients were randomized into 3 study groups; Gp HD, Gp LD, and Gp P as illustrated in Figure 1. A total of 180 patients were included in the current study,60 patients in each study group.

Figure 1. Flow chart of patients’ enrollment and follow up.

The study showed that the 3 groups were comparable regarding age, sex, comorbidities or preoperative ECHO data with p value > 0.05 as shown in Table 1. However, number of smokers was found to be significantly higher in Gp HD compared to Gp LD and GpP as shown in Figure 2 (p value = 0.014).

Table (1): Demographic data and Co-morbidities for the three studied patient groups.

Gp HD: High Dose Group, GP LD: Low Dose Group, GpP: Placebo Group, DM: Diabetes Mellitus, LVEF: Left Ventricular Ejection Fraction, SD: Standard Deviation, Numerical Data are presented as mean ± SD, categorical data are presented as percentage (%).

*Chi-square test. **ANOVA test

Figure 2. Smoking distribution among the 3 studied groups.

• Intraoperative monitoring

The study results revealed that there was no significant statistical difference between both Gp HD and Gp LD groups regarding intra operative data such as number of grafted vessels, aortic cross clamp time, CBP time (p value > 0.05).

Table (2): Intraoperative data parameters monitored for the three different studied groups.

Gp HD: High dose group, Gp LD: Low Dose Group, GpP: Placebo Group, Data are presented as median (range) and mean ± SD

*ANOVA test

3.3. Postoperative inotrope use, ventilation time and early death

Results showed that there was no significant difference in the inotrope use between the three groups postoperatively during the first 24 hours after adjusting smoking as a cofounder using logistic regression (p value = 0.149), as shown in Table 3.

On the other hand, ventilation time was extended for more than 24 hours in both GpP and Gp HD patients groups compared to Gp LD group as illustrated in Table 3, and Figure 3. It is worth to mention that one patient in both Gp HD and Gp LD groups have died in the early postoperative period.

Table (3): Postoperative inotrope use during the first 24 hours , ventilation time and early death in the three studied groups

Data are presented as number (%);

** statistical difference could not be evaluated due to small number of events observed among the 3 studied groups. Gp HD: High Dose Group, Gp LD: Low Dose Group, GpP: Placebo Group

*Chi-square test

Figure 3. Postoperative ventilation time among the 3 studied groups

• Postoperative atrial fibrillation in

A significantly higher proportion of patients in GpP (61.7%) developed POAF in the ICU compared to the other two studied groups (P = 0.009) as demonstrated in Figure 4.

Figure 4. Postoperative atrial fibrillation in ICU for the 3 studied groups.

3.5.  POAF incidence in the 3 studied groups after adjusting smoking status using logistic regression model

The difference in POAF development was adjusted for smoking status in a logistic regression model, as it was the only baseline difference between groups. Results revealed that the proportions of POAF incidence were similar in Gp HD (36.7%) and Gp LD (38.3%) groups (p value = 0.850) as shown in Table 4.

Table (4): Postoperative atrial fibrillation in high dose versus low dose group after adjusting of smoking using logistic regression model.

POAF: post operative atrial fibrillation, Gp HD :High Dose GROUP, Gp LD: Low Dose Group, GpP: Placebo Group

Postoperative ICU stay

The obtained data revealed that the ICU stay was significantly shorter in the Gp LD group compared to the Gp HD (p value < 0.001) and GpP (p value = 0.017). However, there was no significant difference in ICU stay between the Gp HD and GpP groups (p value = 0.905) in Table (5)

Table (5): ICU Length of stay in the three studied groups

ICU LOS: Intensive care unit length of stay, Gp HD :High Dose Group, Gp LD: Low Dose Group, GpP: Placebo Group, ICU: intensive care unit, Data are presented as median (range) and mean ± SD; P<0.05 is considered as statistically significant

*Kruskal-Wallis test (non-parametric ANOVA) test then post-Hoc test

There are conflicting data regarding the protective effect of vitamin C, as an antioxidant, in the prevention of POAF, and consequently its role in shortening the length of ICU and hospital stay ⁸.To the best of our knowledge, most studies were carried out predominantly within a single geographic region, such as Iran. This raises the concerns about the probability of biased research data. It also limits the ability to apply these findings to a broader global population. Although, many studies reported the beneficial activity of vitamin C in POAF prevention, diversity in the recommended dosing regimen of vitamin C for preventing POAF has been observed ¹¹ .

Therefore, our research study employed a randomized controlled trial design to provide patients with different doses of vitamin C, as an antioxidant, after on-pump CABG surgery. Prior to the surgery, the patients were randomly allocated into 3 groups. There were no discernible distinctions between the vitamin C supplementation groups and the placebo group regarding age, gender, diabetes mellitus, hypertension, hyperlipidemia, preoperative medications as well as preoperative ECHO findings regarding left arterial dimensions and left ventricular ejection fraction Also, the preoperative parameters were comparable between the 3 groups. This indicates a baseline similarity prior to intervention, except smoking was found to be a confounder in our analysis

Additionally, intraoperative variables including aortic clamp time and CBP time as shown in exhibited uniformity across the three studied groups. The number of performed grafts suggested a consistent approach to revascularization. This design indicates a standardized intraoperative approach across the three groups, minimizing potential confounding factors related to surgical technique or the duration that related to the incidence of POAF ^14,15.

The postoperative data in our current study exhibited several interesting insights. Following adjustment for smoking as a confounding factor, the requirement for inotropic support 24 hours post-surgery was not significantly different among the three studied groups. This finding showed that vitamin C does not exhibit any influence on the necessity for inotropic medications in the postoperative phase. These findings are found to be in good agreement with what has been reported by Emadi et al. They indicated that the use of vitamin C improved ventricular functions and lowered the levels of cardiac enzymes. However, these effects were observed 72 hours after the surgery while they were not significant during the first 24 hours ¹⁶.

The ventilation time exceeded 24 hours in both GpP and Gp HD compared to the reported low values for Gp LD. This observation is in good accordance to the previously reported study conducted by Hemila H et al. who showed that the ventilation time was reduced by 25% in patients who received vitamin C at a dose of 1-6 grams ¹¹. The possible explanation for reported higher ventilation time in the high dose vitamin C group may be attributed to inter patient variability such as recovery from anesthesia, and overall pre-operative respiratory status which might influence postoperative ventilation requirements.

Regarding the evaluation of ICU stays which provide a valuable insight into the recovery process following CABG surgery, our recorded data shown in established noticeable different findings among the three studied groups. The obtained results demonstrated a significant decrease in ICU stay for patients in the Gp LD compared to both the Gp HD and GpP groups. One possible explanation for this observation might return to lower ventilation time observed in Gp LD. This matches earlier studies that showed a correlation between an extended mechanical ventilation and prolonged ICU stays among adult patients post cardiac surgery who received vitamin C therapy ^17–19 . This, in turn, provides a rationale for the shortened ICU stay specifically in the Gp LD group.

It is worth to mention that effect of vitamin C on morality rate could not be evaluated ; there was only one patient died in the Gp HD group and another one in the Gp LD group during the second and third postoperative days respectively. However, a previous study reported that vitamin C administration for cardiac surgery patients does not impact the mortality rates ⁹ .

In ICU, a notably higher percentage of patients in GpP Group (61.7%) experienced POAF compared to those in both intervention groups as shown in Figure 4. After adjustment for smoking status by a logistic regression model, the incidence of POAF in both Gp HD and Gp LD were comparable as shown in Table 4. Our results are found to be in a good agreement with the study conducted by Polymeropoulos et al. who concluded that high dose vitamin C (2 gm daily) had a significant effect in preventing POAF ²⁰ . Another study reported by Samadikhah et al. also proved the efficacy of lower dose (1gm daily) of vitamin C as a protection from POAF ²¹ .

This study possesses several noticeable points of strengths. First, the study utilized a clinical randomization methodology, enhancing its methodological rigor. Second, patients who regularly received vitamin C supplementation have been excluded from the study. This is considered to be an essential precaution, as vitamin C supplementation could potentially act as a hidden variable influencing the incidence of POAF ⁷ . Third, as age is a recognized independent risk factor for

POAF, the study has focused on elderly patients. Forth, our study was the first Egyptian study, which investigated the effect of different dosage regimen of vitamin C in prevention of POAF.

Finally, our study has some limitations. This study has successfully examined the effect of only one antioxidant in the prevention for POAF. Therefore, further studies are still needed to investigate the effect of other antioxidant such as vitamin D and magnesium as potential antioxidants for POAF prevention.

Administration of oral doses of vitamin C before and after CABG in either high dose (2gm/day) or low dose (1gm/day) has proven to exhibit a protective effect in mitigating and preventing POAF alongside with beta-blockers and statins. However, vitamin C shows a minor role in reducing the ICU stay length after CABG surgery. This could be attributed to the presence of multiple factors influencing ICU stay length, not solely related to the presence of POAF, particularly ventilation.

Recommendations

Oral Vitamin C in 1gm daily should be included as supplement for prevention of POAF in elderly patient undergoing CABG surgery.

Acknowledgment: We express our gratitude for the valuable support offered by Rana Mostafa Adel, Lecturer of Molecular Biology in the Zoology Department at the Faculty of Women for Arts, Science, and Education, Ain Shams University. We appreciate her efforts in proofreading and enhancing the language of the manuscript.

Conflict of interest: There is no conflict of interests to declare.

Contributions of Authors statement

All authors contributed to the study's conception, design, material preparation, data collection, data analysis, and the writing of the manuscript.

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