Preoperative and postoperative administration of vitamin C in cardiac surgery patients – settings, dosages, duration, and clinical outcomes: a narrative review

Vitamin C or ascorbic acid is a water-soluble vitamin capable of directly donating electrons to reactive oxygen species, attenuating electrical remodeling, and cardiac dysfunction in patients undergoing cardiac surgery (CS), considered one of the most effective defenses against free radicals in the blood, thus being one of the first antioxidants consumed during oxidative stress. The aim of this review is to assess the effects of perioperative administration of vitamin C in CS patients. A comprehensive literature search was conducted in order to identify prospective cohort studies and/or randomized controlled trials reporting on the perioperative effects of vitamin C among adult patients undergoing CS. Studies published between January 1980 to December 2022 were included in our search, resulting in a total of 31 articles that met all our inclusion criteria. There seems to be a beneficial effect of vitamin C supplementation in arrhythmias such as in postoperative atrial fibrillation, reduction of ICU length of stay, and hospital length of stay, reduction in postoperative ventilation time, in inotropic demand, and in postoperative fatigue. Vitamin C can act as a scavenger of free radicals to decrease the peroxidation of the lipids present in the cell membrane, and to protect the myocardium postoperatively from ischemia/reperfusion injury, thus attenuating oxidative stress and inflammation. It represents a readily available and cost-effective strategy that could improve the outcome of patients undergoing CS, by reducing the risk of serious cardiovascular adverse events, both perioperatively and postoperatively.


Introduction
Vitamin C or ascorbic acid (AA) is a water-soluble vitamin that has stimulated widespread scientific interest, since its discovery, thanks to its various functions [1] within the human body, impacting nervous, respiratory, renal, and cardiovascular systems, as well as coagulation, hemoglobin formation, inflammation, and immunomodulation (Table 1) [14,38,39] .Vitamin C is a lactone, comprising 6 carbon, 8 hydrogen, and 6 oxygen molecules linked with double and single covalent bonds (C6H8O6) [40] and acts as an electric donor (or reductant) in over 60 enzymatic pathways [41] .Different studies reveal its contribution to the reduction of oxidative stress and organ dysfunction making it widely known as one of the most significant HIGHLIGHTS • In the current review (31 articles), we summarize the effects of preoperative and postoperative administration of vitamin C among adult cardiac surgery (CS) patients.• There is a reduction of plasma concentration of vitamin C after a CS and needs to be substituted.• Vitamin C attenuates oxidative stress and inflammation, thus protecting myocardium from ischemia/reperfusion injury.• There is evidence for a beneficial effect of vitamin C supplementation in arrhythmias such as in postoperative atrial fibrillation, reduction of ICU length of stay, and hospital length of stay, reduction in postoperative ventilation time, in inotropic demand, and in postoperative fatigue.• Substitution of vitamin C postoperatively, is a strategy that could improve the outcome of patients undergoing CS.
antioxidants [12] .Its chemical structure can explain its antioxidant effects and its ability to control the intracellular redox equilibrium [42] , protecting cells and organs from damage to macromolecules [43] .It leads to the formation of semidehydro-AA, which is a stable acid that is further metabolized and discharged [5] .The ascorbate anion (ASC), through its interaction with glutathione (GSH) [42,[44][45][46][47] , can directly donate electrons to reactive oxygen species (ROS), such as O = O singlet oxygen, superoxide anions, hydroxyl radicals, and tocopheroxyl radicals [48] .This spontaneous electron provision to free radicals eliminates them efficiently [47] and therefore relieves the oxidized cellular environment caused by aerobic metabolism.
Consequently, vitamin C attenuates electrical remodeling and this is crucial, as structural and electrical modifications that are generated by oxidative stress are substrates for cardiac dysfunction [49] .
In the human body, vitamin C cannot be synthesized [50] , so it is provided entirely through the diet [51] and is mainly acquired by the consumption of fruits (especially citrus), vegetables, and supplements [52] .Its molecular weight is 176.12 gr/mol (1 mg = 5.7 μmol) [53] and for healthy adults, a regular diet should include 40 mg of vitamin C per day [currently established recommended dietary allowance (RDA)] [54] .Current evidence suggests that low levels of vitamin C correlate with inflammation [C-reactive

System
Effects of vitamin C

Cardiovascular system
Attenuates myocardial damage and improves myocardial stunning [2] .
Facilitates enteral uptake of non-heme iron, and reduction of folic acid [1] .Eye health Slows down the progression of advanced age-related macular degeneration and loss of visual acuity [16] .Protects against cataract [17] .
Decreases postoperative pain and prevents complex regional pain syndrome (CRPS) following orthopedic procedures [24] .Reduce the feeling of fatigue in patients with cancer or inflammatory diseases [25] .

Nervous system
Elevated levels protect neurons from oxidative damage [2] .Reduces the infarct volume after ischemia [26,27] .Contributes to the myelination of the neurons [28] .Acts as a cofactor in neurotransmitter synthesis [29] .

Renal system
Reduces fluid demand and increases urine production [30,31] .Protects kidney function and renal arterial reactivity against IRI [32] .Decreases resistance index of the renal artery [32] .
Participates to the treatment of acute respiratory infections and to the mitigation of inflammation in critical COVID-19 patients [35] .

Reproductive system
Protects spermatogenesis, plays a major role in semen integrity and fertility, and prevents sperm agglutination [36] .
Plays key role in the synthesis of testosterone [36] .Minimizes alterations in the male reproductive system caused by hyperglycemia [37] .
protein (CRP)], suggesting for high vitamin C consumption during oxidative stress.Low levels of vitamin C may be a risk marker of organ dysfunction (Table 2) [26,48,49,65] as low levels are identified in patients with sepsis, hemorrhage, multiple organ failure, stroke, traumatic brain injury, and in patients undergoing cardiac surgery (CS) [66] due to rapid leukocyte turnover and higher cellular consumption.This is interpreted by the fact that intracellular ascorbate concentrations in granulocytes and mononuclear leukocytes are 25 and 80 times higher than in plasma, respectively [1,47,48,67,68] .The physiologic levels of this micronutrient may be restored by intravenous vitamin C treatment, and/or high oral supplementation.Studies propose that people undergoing surgery require more than 500 mg of vitamin C per day, to prevent associated complications, while those who are under a lot of stress require even higher doses [69] .Even though, vitamin C is considered as a first-line supplement [22,[70][71][72] , its clinical use and therapeutic effectiveness for patient recovery and improvement of long-term clinical outcomes in CS patients is still under investigation [73][74][75][76][77] .Therefore, in the current review, we sought to summarize the effects of preoperative and postoperative administration of vitamin C among adult CS patients.Abbreviations and acronyms used throughout this manuscript are explained in Table 3.

Materials and methods
A comprehensive literature search was conducted in four major electronic databases (Medline/PubMed, Cochrane Library, Embase/Elsevier, and Google Scholar) in order to identify prospective cohort studies and/or randomized controlled trials (RCTs) reporting on the preoperative and postoperative administration of vitamin C among CS patients.The search covered the period between January 1980 to December 2022.
Predefined search terms included 'vitamin C', 'ascorbic acid', 'ascorbate' and 'cardiac surgery', 'cardiothoracic surgery', 'heart surgery', 'cardiopulmonary bypass', 'CPB', 'extracorporeal circulation', 'ECC', 'coronary artery bypass grafting', 'CABG', 'CAB', 'valve surgery', and 'valvular surgery'.There was no language limitation.Studies that were included in the analysis met the following criteria: (i) prospective cohort studies and/or RCTs, (ii) adult patients ( > 18 years old) undergoing CS, (iii) comparison of antioxidant vitamin C with a control or placebo group, (iv) studies that reported data on the preoperative and/or postoperative administration of vitamin C (duration and dosage), and (v) studies that reported information on the incidence of postoperative complications following administration of vitamin C in adult CS patients.
Studies were excluded if they reported on nonadult patient populations (< 18 years old).Review articles focusing on the topic were excluded, however, the reference list of all review articles identified, was searched in order to include any additional original articles that met the inclusion criteria and were not identified through the extensive databases' search.

Results
In brief, a total of 132 published articles were identified through the initial literature search from the four major electronic databases.Following the abstract review, we excluded 101 manuscripts that did not include clinical events based on the principal inclusion and exclusion criteria.The 31 remaining articles were examined in full-text and included in the present narrative review

System
Consequences of vitamin C deficiency

Respiratory system
More susceptible to severe respiratory infections such as pneumonia [35,58] .

Reproductive system
Reduction in reproductive performance [36] .

Athanasiou et al. Annals of Medicine & Surgery (2024)
since they met our inclusion criteria.All enrolled studies reported on vitamin C administration regimens (solely or amongst with other antioxidants) as well as on the preoperative and postoperative effects among CS patients: namely the clinical setting, dosages, duration, potential complications, and/or the primary or secondary clinical outcomes.A detailed list of the enrolled studies with their characteristics and outcome measures (OMs) is presented in Table 4.
There are only a handful of studies that give us an insight into the changes in plasma vitamin C concentrations following cardiac or more specifically coronary artery bypass grafting (CABG) surgery, as presented in Table 5.In these studies, the levels of plasma AA in mg/l or μmol/l were measured preoperatively as baseline measurements, and followed up for 6 h, up to 1-day, 2 days, or 14 days perioperatively and postoperatively.The pattern of plasma changes in all studies is surprisingly the same even after 2 weeks postoperatively.There is a reduction of plasma vitamin C following cardiopulmonary bypass (CPB), namely more than 50%, 6 h postoperatively, and the lower levels persist for up to 14 days [38,73,75,[99][100][101] .Our search retrieved no study in the literature that examines vitamin C levels beyond the 2 weeks postoperatively in CS, neither has examined the effects of a longer-term supplementation in this group of patients.We hereby assume that since vitamin C is obtained entirely from diet, the vitamin C low plasma levels and in some cases even marginal deficiency [75] , will persist for weeks or even for longer periods if patients are undernourished or receive inadequate amounts of vitamin C supplementation.This can inevitably predispose this group of patients to the risks accompanying vitamin C low plasma levels or even deficiency, for example, progression of atherosclerosis [58] with increased risk of coronary heart disease [15,55,56] and even acute myocardial infarction (MI) [15] .

Characteristics and clinical settings of vitamin C studies
Vitamin C in the context of CS has been under investigation since the early beginning of the modern CS era in the late 60s.In our review, the literature extends from 1981 up to 2020.The geographic expansion of the studies includes almost all continents (North America, South America, Africa, Europe, Asia, and Australia).Notably there are far many studies from the Middle East, namely from Iran.The vast majority of the included studies were CABG operations with CPB.Depending on the various authors' inclusion and exclusion criteria, clinical endpoints and scientific aspirations, sole valve/valves, or combined operations with CPB, and sparse off-pump CABG were met, all of which in notable smaller numbers and in fewer studies than those with sole CABG with CPB.
In the majority of studies, vitamin C was administered solely, whereas in some studies it was administered alongside with other antioxidants and/or anti-inflammatory or antiarrhythmic agents under various regimens.Amongst the standard of care for CS patients, n-3 polyunsaturated fatty acids (n-3 PUFAs) and/or vitamin E were used in various therapeutic schemes.Interestingly, the only two Scandinavian studies we have from Angdin et al. [79] and Sisto et al. [94] have implemented allopurinol in addition to vitamins C and E. The rationale of this combination is allopurinol's ability to indirectly inhibit ROS generation [102] , thus acting as an antioxidant [103] , and theoretically conferring additive antioxidant capacity to the regimen.
Preoperatively, most of the studies used a single dose of 2 g of vitamin C with some variations among authors, especially among those administering combined therapies that followed no special pattern.Postoperatively, a smaller dosage of 1 g/day or less, was administered for some postoperative days, most frequently for 5 days.In general, vitamin C was administered in somewhat higher doses preoperatively and for shorter periods than postoperatively.There was only one author that administered solely vitamin C for up to 14 days postoperatively [90] .Rodrigo [96,97] and Castillo et al. [49] in their combined regimens (vitamins C and E and n-3 PUFAs) continued the regimen until hospital discharge.However, single dosages as high as 250 mg/kg have also been reported [43] .To our knowledge, there is no dose-finding study on CS patients yet.

Cardio-protective effects of vitamin C
In patients with atherosclerosis, there is biochemical evidence suggesting increased oxidative stress, which results from an altered balance of endogenous pro-oxidants and antioxidants [104][105][106] .Vitamin C, the major water-soluble antioxidant in human plasma, has been shown to reverse endothelial dysfunction [107] in patients with ischemic heart disease [108,109] by restoring vascular responsiveness to vasoconstrictors [110] while inhibiting nitric oxide (NO)-induced resistant vasodilation [10] .At the same time, it protects against oxidative stress-induced pathological vasoconstriction and protects against the loss of the endothelial barrier thereby preventing the depletion of endothelial nitric oxide (eNO) [1] .In vivo, ascorbate can directly inhibit platelet-endothelial adhesion in capillaries through its' hemodynamic effects on capillary blood flow [10] .These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis, scavenging free radicals, and sparing endothelial cell-derived nitric oxide, thus playing a beneficial role in endothelial growth, survival, function and maintenance of vascular responsiveness, and integrity [44] .Low-density lipoprotein (LDL) cholesterol in the blood can only be significantly atherogenic after oxidative modification, which allows it to be taken up by macrophages in the artery walls.Antioxidants such as vitamin C can protect LDL from oxidative modification and can help prevent coronary artery disease (CAD) [111] .
In the cardiovascular system, vitamin C is essential for the biosynthesis of noradrenaline, cortisol, angiotensin, and hormones that are vital for maintaining adequate vascular tone for the perfusion of various organs [4,112] .Ascorbate-dependent synthesis of vasopressors represents a plausible physiological mechanism whereby ascorbate could act as adjunctive therapy for severe sepsis and septic shock [112] .Observational studies have shown an inverse relationship between plasma vitamin C concentrations and peripheral arterial disease (PAD) [66] or blood pressure [113,114] as well as an inverse relationship between vitamin C intake and CAD mortality [115,116] , cerebrovascular events [117,118] , or PAD [119] .
The whole-body inflammatory response produced by CPB is a major pathogenetic cause for postoperative complications after cardiac procedures, and induces both oxidative stress and systemic inflammatory response [120][121][122] .The inflammatory response has been shown to produce a large number of ROS, cytokines, and other cytotoxic materials [89] .Re-exposure of tissues to ROS at the end of CPB produces the so-called 'ischemiareperfusion injury' (I/R) [123] .These aggressive oxygen species can damage various cellular components and the damage can be continued by a chain reaction of peroxidation of PUFAs [124] .However, a multiple defense systems, including enzymes (e.g.superoxide dismutase), endogenous antioxidants (e.g.glutathione and serum proteins), and exogenous dietary antioxidants (e.g.vitamin C and E and carotenoids) [12] , protects the body from injuries caused by ROS [95,124] .Following reperfusion, the patient's own natural antioxidant defense mechanisms prevent the release of free radicals.This implies the consumption of antioxidant nutrients, such as vitamins A, C, and E, selenium, glutamine, and zinc [12] .Depletion of these protective vitamins may potentially cause deleterious effects of ROS on organs' functions after CPB.Based on its redox-potential and powerful antioxidant capacity, vitamin C, has been called 'the most important antioxidant', as it counters the influence of free radicals in the blood in the most effective way [125,126] , as well as it is the first antioxidant consumed during the oxidative stress, therefore sparing other endogenous antioxidants [125,126] .The finding of substantial vitamin C consumption suggests that a perioperative/postoperative vitamin C supplementation, in combination with other antioxidants, may moderate the whole-body inflammatory response and thereby reduce morbidity associated with CPB and CS [3,33,43,127,128] .Consequently, vitamin C is a Angdin [79] 2003 In cardiac patients receiving antioxidants the endothelium-dependent vasodilation was better maintained after surgery Antonic [80]  Antonic [81] 2017 NS protective effect of AA on the incidence of postop AKI.Limitations: sample size was relatively small with only 100 patients included, short-term, (5 postop days), single-center trial.
Oxidative stress associated with heart failure (HF) leads to depletion of vitamin C [133][134][135] .Therefore, it has been proposed that vitamin C plays a role in HF therapy [136] by restoring heart's ventricular function [12] .There are many studies revealing its effects on the heart's mechanical efficiency and contractility as assessed by LVEF (left ventricular ejection fraction) measurements [137][138][139] .Firstly, as shown in a meta-analysis conducted by Hemila et al [140] ., vitamin C increased LVEF in both cardiac and noncardiac patients on average by 12 and 5%, respectively.Additionally, Shinke et al. observed that in people suffering from HF due to previous MI, administration of vitamin C improves the response of LV contractility and LV stroke work to adrenergic stimulation and thereby restores myocardial efficiency [141] .These results are also reinforced by the RCT conducted by Qin et al. [142] who documented that vitamin C attenuated LV dilation and dysfunction in HF following MI through diminishing oxidative stress and reducing myocyte apoptosis.Moreover, Hornig's et al. [143] research demonstrated that long-term oral administration of vitamin C may improve endothelial dysfunction in congestive HF patients.Seemingly, alongside the conventional and newer therapeutic agents used for the treatment of HF [144,145] , vitamin C can have a beneficial role.
Though not consistent in all authors, there seems to be a beneficial effect of vitamin C supplementation in arrhythmias such as in POAF/flutter, reduction of ICULOS and HLOS, reduction in postoperative ventilation time, inotropic demand, and quite interestingly less postoperative fatigue.Gholami et al. [25] found that immediately after CABG surgery, antioxidants with vitamin C can effectively improve patients' general and physical fatigue as well as improve reduced activities and motivation to live.Sadeghpour et al. even reported less drainage volume in the first postoperative day (POD -1) for the vitamin C group.An additive beneficial effect with regards to the reduction of postoperative arrhythmias was observed with simultaneous supplementation of vitamin C and b-blockers [83,87,91] , while Samadikhah et al. [93] reported the same beneficial effect for the combination of atorvastatin plus vitamin C, than single oral atorvastatin.
While Dingchao et al. [43] suggested that vitamin C can act as a scavenger of free radicals to decrease the peroxidation of the lipids present in the cell membrane and remove the radicals to effectively protect the myocardium I/R injury during and after open heart surgery, Jouybar et al. [89] on the other hand, claimed that vitamin C has no effect on the reduction of inflammatory cytokines (IL6 and IL8) during CPB [89] .Nevertheless, the results from the Westhuyzen trial regarding the reduction of myocardial damage evaluated with ECG and single photon emission computed tomography (SPECT), in patients treated with vitamin C, were not proven to be statistically significant [98] .
Lastly, a number of combination studies that included vitamin C resulted in various promising findings [49,[94][95][96][97] .Sisto et al., showed that a combination therapy with allopurinol, vitamin C, and vitamin E inhibited ischemic ECG alterations and protected against post-CABG arrhythmias.In the same study, the aforesaid therapy proved to be able to reduce postop MI in high-risk patients, while showed a trend for reduced vasopressor demand postoperatively as well as lower CK-MB release in groups treated with antioxidants and allopurinol compared to controls [94] .Stanger et al. administered a combination of vitamins C & E & n-3 PUFAs and examined serum oxidative stress biomarkers and oLAb.He found that water-and lipid-soluble antioxidants, significantly decreased at the 1st and 2nd postoperative days in all study subgroups but recovered at the 3rd postoperative day.The authors documented that vitamins C and E supplementation was associated with a significant decrease in total peroxides both in the vitamin as well as in the vitamin + n-3 PUFAs groups as compared to controls and n-3 PUFAs alone, thus concluded that the administration of vitamins C and E attenuates postop Hill [38] 2019 Pros 34 Plasma AA (VitC) CABG w/ CPB 2 days Reduced from 6.5 (3.5-11.5)mg/l to 2.8 (2.0-3.9)mg/l Rodemeister [73] 2014 Pros 29 Plasma AA (VitC) Cardiac w/ CPB 6 days Reduced from 61.5 ± 18.6 μmol/l to 28 ± 11.5 μmol/l Valle-Giner [99] 2007 Pros 27 Plasma AA (VitC) Cardiac w/ CPB 6 h Reduced from 43 ± 3 μmol/l to 18 ± 2 μmol/l Lassnigg [100] 2003 RCT 20 (placebo) Plasma AA (VitC) Cardiac w/ CPB 6 days Reduced from 9.72 ± 4.71 mg/l to 4.65 ± 2.12 mg/l Ballmer [75] 1994 RCT 9 (control) Plasma AA (VitC) CABG w/ CPB 1, 14 days Reduced from 36 ± 19 μmol/l to 10.5 μmol/l (1-day) and 19.1 μmol/l (14 days) Cavarocchi [101] 1986 RCT 20 (control) Plasma AA (VitC) Cardiac w/ CPB 1-day Reduced from 16 ± 3 mg/l to 6.6 ± 2.3 mg/l oxidative stress during CABG [95] .The same combination was examined by Rodrigo et al. [96] , who found that the antioxidant supplementation with n-3 PUFAs and vitamins C and E resulted in a more marked reduction of POAF in older patients.The same author in another study with the same combination of supplements showed that this safe, well-tolerated, and low-cost regimen favorably affected POAF, increased antioxidant potential, and attenuated oxidative stress and inflammation [97] .

Adverse health effects
Vitamin C's pharmacokinetics is complex and its plasma concentration depends on absorption, tissue transportation, volume distribution, cellular uptake, consumption (rate of utilization), and renal reabsorption and excretion [146] .The concentration dosage curve has a sigmoidal shape.Its steep portion ranges between 30 mg and 100 mg of daily vitamin C and 70 to 85 μmol/ l are plasma concentrations plateau.Additional increases in plasma concentrations are minimal at dosages larger than 400 mg/day [147] .Overall, at maximum oral intake, plasma concentrations of vitamin C do not exceed 220 μmol/l.At plasma concentrations below 20 μmol/l, symptoms of vitamin C insufficiency appear such as fatigue and/or irritability, and concentrations under 11 μmol/l result in a condition known as Scurvy [22] .Although uncommon, side effects of vitamin C supplementation have been reported in the literature.These possible adverse effects depend on dosage, route of intake, and frequency and duration of vitamin C supplementation [22,148] .Doses greater than 1000 mg per day may cause diarrhea, abdominal bloating, and kidney stones.However, from the short-term use of vitamin C, no significant adverse effects have been reported, especially for high doses up to 200 mg/kg/day (15 g per day) and even for the higher reported dosages of 1500 mg/kg three times per week (100 g of vitamin C) in cancer patients [2] .From a survey of 9328 patients who used high-dose intravenous vitamin C for 12 months, only a small percentage (101 side effects), most of them minor, were reported including lethargy/fatigue in 59 patients, change in mental status in 21 patients, and vein irritation/phlebitis in six patients [148] .The authors in the studies of our review have not reported any complications or AEs attributed to vitamin C therapy, neither solely, nor in combination with other antioxidants.

Study limitations
By design, our narrative literature review is not systematic and follows no specified standards or protocols, nor a relevant metaanalysis is conducted.Although this type of review has inherent limitations in terms of objectivity, completeness of literature search, and interpretation of findings, as it is much more prone to selection and other biases, we tried to our best to be objective and arrive at a comprehensive understanding of the state of the science related to the problem.Even though our review is evidencebased, as a narrative review, is not always considered massively helpful in terms of the scientific evidence it brings.A future systematic review of RCTs and a meta-analysis could definitely address more comprehensively the postoperative administration of vitamin C in CS patients.

Conclusion
In summary, our narrative review identified a number of prospective cohort studies and RCTs which show that vitamin C is a safe and affordable supplementation therapy that may help in various patients who are undergoing CS or other cardiac procedures.Vitamin C reduces the risk of significant cardiovascular complications and costs, both during the hospital stay and potentially for up to the first 1-2 months after surgery.This is particularly beneficial because remodeling and restoration of the heart's muscle and nerve tissue occur during the same period of time.
Several research questions remain under consideration.Should vitamin C be administered routinely in CS patients?Has vitamin C a place in CS perioperative and postoperative optimal therapy?Which patient population could benefit most from this regimen?For how long, in which dose and by which route should it be administered?Should vitamin C be administered solely or in a combination with other antioxidants and/or other medications?Future investigations need to address such scientific questions through more sophisticated RTCs, preferably organized as multicenter studies, adequately powered, well stratified, and blinded, in order to enlighten the present knowledge gap about the use of vitamin C postoperatively, following CS.A postoperative vitamin C supplementation study that extends beyond the first 5-7 postoperative days, namely during the period of tissue remodeling, up to 4-6 weeks postoperatively, has not been conducted so far.Therefore, the potential of possible clinical benefits from such an intervention remains unclear.Taking into consideration the current evidence, one can hypothesize, that vitamin C supplementation for this longer period might benefit CS patients in ways that have not been previously reported in the scientific literature.This potentially paves the way for improvements in the therapeutic strategy for certain groups of CS patients, and subsequently a more efficient clinical approach.

Ethical approval
This is a narrative literature review manuscript.Ethical approval is not applicable to this review.

Consent
This is a narrative literature review manuscript.Informed written consent is not applicable to this review.

Table 1
Summary of vitamin C influence on different systems

Table 2
Consequences of vitamin C deficiency on different systems.

Table 3
Abbreviations and acronyms used in the review

Table 4
Characteristics of studies included in the reviewAuthor, year of publication, country, type of study, OP type, study groups, mean age (Years), male sex (♂) : adults undergoing elective CS, PVRI before surgery decreased by > 5% after infusion of Ach.EC: DM, treated with acetylcysteine, allopurinol, and vitamins C and E. StR: Group 1: 900 mg VitE daily for 10 to 14 days before surgery plus 2 g Vit C and 300 mg allopurinol the evening before surgery plus 300 mg VitE, 2 g VitC, and 600 mg allopurinol on the day of surgery.During surgery infusion of Ach until 2 h after surgery.Group 2: only Ach.Group 3: no Ach (but saline).

Table 4 ( Continued )
Author, year of publication, country, type of study, OP type, study groups, mean age (Years), male sex (♂) : women of premenopausal age, MI, use of study medicines during 30 days before CABG, renal (Cr > 150 ~g/l) or hepatic (AST > 40 IU/l) disease, allergy to study medicines.StR: Stable or low risk disease: EC VitC: 2/37-5.4% |Control: 10/35-2.8.5%, P = 0.0076 Patients > 60 years present higher levels of lipid peroxidation, lower enzymatic activity of GSH-Px and decreased total antioxidant plasma capacity.Patients with POAF showed higher plasma MDA levels postop and lower atrial GSH-px activity OM: POAF until hospital discharge, Activity of antioxidant enzymes: Cu-Zn superoxide dismutase, catalase and GSH-Px activities, Plasma MDA compared with those who did not present POAF (P < 0.01).Antioxidant supplementation resulted in a more marked reduction of POAF in older patients.It could be suggested that the efficacy of this therapy improves with ageing ≥ 18 years old, scheduled for CABG or/and valve surgery, sinus rhythm.EC: history of any arrhythmia, previous MI, use of amiodarone or sotalol, severe CHF (NYHA III or IV), prosthetic valves, congenital valvular disease, left atrial diameter > 50 mm, conditions associated with oxidative stress or inflammation such as chronic rheumatic or neoplastic diseases, liver insufficiency, severe chronic kidney disease (serum Cr > 2.0 mg/dl), recent infections, use of NSAID, corticosteroids, antioxidant vitamins, or fish oil supplements 3 m preop.

Table 5
Studies assessing changes in vitamin C following surgery