European Journal of Cardiovascular Medicine

Vasoplegic syndrome, a form of vasodilatory shock following cardiopulmonary bypass (CPB), may affect up to half of all patients undergoing major cardiovascular surgery. The pathophysiology of vasoplegic syndrome is similar to that of sepsis. A large number of patients require vasopressors post-operatively to maintain adequate tissue perfusion. The need for escalating vasopressors is associated with a higher incidence of morbidity and mortality. Vasoplegia is characterized by a normal or augmented cardiac output with low systemic vascular resistance (SVR), causing organ hypoperfusion. The exact definition has varied, but it is typically considered when shock occurs within 24 h of CPB in the setting of a cardiac index (CI) greater than 2.2 L/kg/m2 and SVR less than 800 dyne s/cm5. These criteria are relatively non-specific and found in other disease states such as sepsis, adrenal insufficiency, and hepatic failure. Among others, with the distinction being the etiology of the shock (infection in the case of sepsis and exposure to extracorporeal circulation in the case of vasoplegia). Treatment of this syndrome is usually limited to the initiation of vasopressors to maintain adequate perfusion pressures via the targeting of a specific mean arterial pressure (MAP). Due to the similarity between vasoplegic syndrome and sepsis, along with paucity in supporting evidence, many of the treatment options used in septic shock have been extrapolated to use in vasoplegic syndrome. Vitamin C (ascorbic acid or ascorbate) is an essential water-soluble micronutrient that humans must obtain through dietary sources due to the evolutionary loss of the enzyme L-gulonolactone oxidase, which is required for its endogenous synthesis [1]. The recommended daily allowance (RDA) for vitamin C in adults ranges between 75–100 mg/day, sufficient to maintain plasma concentrations of approximately 50–60 μmol/L under normal physiological conditions [2]. However, certain tissues-such as leukocytes, adrenal glands, the brain, and the eyes-accumulate vitamin C at concentrations up to 100-fold higher than plasma levels, highlighting its critical role in immune function, neuroendocrine regulation, and antioxidant defense [3]. Vitamin C serves as the body’s primary water-soluble antioxidant, effectively scavenging reactive oxygen species (ROS) such as superoxide (O₂⁻), hydroxyl radicals (OH⁻), and peroxynitrite (ONOO⁻), thereby protecting cellular components from oxidative damage [4]. Beyond its direct free radical-neutralizing properties, vitamin C acts as an essential cofactor for numerous enzymatic reactions, including the biosynthesis of catecholamines (norepinephrine, epinephrine, and dopamine), vasopressin, and collagen, as well as the modulation of hypoxia-inducible factor (HIF)-1α stability [5,6]. Additionally, it plays a pivotal role in regenerating other key antioxidants, such as α-tocopherol (vitamin E), glutathione, and urate, thereby amplifying the body’s overall antioxidant capacity [7]. Its anti-inflammatory effects are mediated through the inhibition of nuclear factor-kappa B (NF-κB) signaling, reducing the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [8]. Furthermore, vitamin C enhances endothelial function by preserving nitric oxide (NO) bioavailability, reducing endothelial permeability, and preventing microvascular leakage and edema effects that are particularly relevant in conditions of systemic inflammation and ischemia-reperfusion injury [9]. Cardiac surgery involving cardiopulmonary bypass (CPB) is associated with a profound systemic inflammatory response and oxidative stress due to blood contact with artificial surfaces, ischemia-reperfusion injury, and hemodilution [10]. These processes lead to a rapid and sustained depletion of circulating vitamin C, with levels often falling below 50% of baseline within hours of CPB initiation and remaining low for several days postoperatively [11]. This deficiency may contribute to the development of vasoplegic syndrome, a well-recognized complication following cardiac surgery characterized by severe hypotension, decreased systemic vascular resistance, and reduced responsiveness to catecholamines, often necessitating high-dose vasopressor support. The underlying mechanisms include endothelial dysfunction, NO overproduction, and adrenergic receptor desensitization, all of which may be exacerbated by oxidative stress and vitamin C deficiency. Given vitamin C’s role in catecholamine synthesis, endothelial protection, and antioxidant defense, there is growing interest in its therapeutic potential for mitigating vasoplegia and reducing vasopressor requirements in post-CPB patients. Preliminary studies in septic shock have demonstrated that high-dose intravenous vitamin C reduces vasopressor dependency and improves hemodynamic stability, suggesting a possible benefit in cardiac surgery patients as well. However, robust clinical evidence in the context of CPB remains limited, and the optimal dosing regimen has yet to be established. The primary objective of this study is to evaluate the effect of intravenous vitamin C administration on the total dose of noradrenaline required postoperatively in patients undergoing CPB. The secondary objectives include assessing the time to weaning from noradrenaline, the length of intensive care unit (ICU) stay, and ICU mortality.

This study was a prospective, randomized, double-blind, placebo-controlled trial conducted at the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar, India. The study protocol was reviewed and approved by the Institutional Research Ethics Committee (IREC) of IGIMS (Reference No: 678/IEC/IGIMS/2022), in compliance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Written informed consent was obtained from all participants before enrollment.

Inclusion Criteria:

·         Age: 20–60 years.

·         Sex: Patients of either sex.

·         Surgical Procedure: Isolated mitral valve replacement (MVR) or aortic valve replacement (AVR) under cardiopulmonary bypass (CPB).

·         Body Weight: 40–60 kg.

·         Hemodynamic Requirement: Postoperative vasoplegia necessitating noradrenaline infusion for hemodynamic support.

Exclusion Criteria:

·         Complex Valve Surgery:

Ø  Dual valve replacement (e.g., combined MVR + AVR).

Ø  Combined cardiac procedures (e.g., valve + coronary artery bypass grafting).

·         Severe Cardiac Dysfunction: Preoperative left ventricular ejection fraction (LVEF) <30%.

·         Age Restrictions:

Ø  Pediatric patients (<20 years).

Ø  Elderly patients (>60 years).

Patient Declination: Lack of informed consent or refusal to participate.

·         High-Risk Conditions:

Ø  Emergency or salvage surgery.

Ø  Pre-existing vitamin C supplementation (within 7 days before surgery).

Ø  Severe renal (eGFR <30 mL/min) or hepatic dysfunction (Child-Pugh class B/C).

Ø  Known hypersensitivity to ascorbic acid.

Patient Population and Randomization:

Eligible participants included adult patients scheduled for elective open-heart surgery involving mitral valve replacement (MVR) or aortic valve replacement (AVR) under cardiopulmonary bypass (CPB). Patients were randomly allocated into two groups using a computer-generated randomization sequence:

·         Group I (Vitamin C Group): Received 2 grams (8 mL) of intravenous vitamin C at the time of weaning from CPB, followed by a second dose of 2 grams (8 mL) on the first postoperative day.

·         Group II (Placebo Group): Received an equivalent volume (8 mL) of normal saline (0.9% NaCl) at the same time points.

To ensure blinding, the study solutions (vitamin C and placebo) were prepared by an independent pharmacist and administered in identical opaque syringes.

Intervention Protocol:

·         Vitamin C Preparation: A sterile solution of ascorbic acid (500 mg/mL) was diluted in normal saline to achieve the required concentration.

·         Placebo: Normal saline (0.9% NaCl) was used as the control.

·         Both groups received standard perioperative care, including anesthesia, CPB management, and postoperative ICU protocols, as per institutional guidelines.

Sample Size:

A power analysis was made by using G*power software, version 3.0.1 (Franz Foul Universitat, Kiel, Germany). A sample size of 44 patients required in each group would yield 80% power to detect significant differences, with an effect size of 0.50 and a significance level of 0.05. Assuming a 10% dropout rate, we enrolled 48 patients in both groups.

Statistical Analysis:

The collected data was organized into a table using Microsoft Excel 2019. Subsequently, the data were transferred to Graph Pad version 8.4.3 for further statistical analysis. Continuous variables were compared using Student’s t-test or Mann-Whitney U test, while categorical variables were assessed with Chi-square or Fisher’s exact test. A difference was deemed significant if the p-value was less than 0.05.

The study analyzed 88 patients undergoing cardiac valve surgery, evenly distributed between the Vitamin C group (n=44) and placebo group (n=44). Preoperative evaluation demonstrated comparable baseline characteristics between groups regarding demographic profile, comorbidities, and echocardiographic parameters. Intraoperative monitoring revealed similar procedural details and time parameters across both cohorts.

Post-cardiopulmonary bypass hemodynamic management showed statistically significant differences between treatment arms. The Vitamin C group demonstrated superior outcomes, with only 38.6% (17/44) requiring vasopressor support compared to 68.2% (30/44) in the placebo group (p=0.004). Resolution of vasoplegia occurred significantly faster in the Vitamin C cohort (14.4±4.6 hours vs 24.6±7.2 hours, p<0.001). Hemodynamic stability was more rapidly achieved, as evidenced by higher mean arterial pressures immediately post-CPB (93.2±22.8 mmHg vs 81.1±28.6 mmHg, p=0.035).

Clinical outcomes further favored the Vitamin C intervention group. The duration of intensive care unit stay was significantly shorter among Vitamin C recipients (4.1±1.8 days vs 5.2±2.3 days, p=0.017). Mortality rates showed no statistically significant difference between groups (1 vs 2 cases respectively, p=0.555).

These findings demonstrate that high-dose Vitamin C administration effectively reduces vasopressor requirements in post-cardiopulmonary bypass vasoplegia. The intervention significantly improved hemodynamic parameters, accelerated recovery from vasoplegic shock, and decreased ICU length of stay. Vitamin C emerges as a valuable non-vasopressor adjunct in managing this challenging postoperative complication, potentially through its multifaceted effects on endothelial function, catecholamine synthesis, and oxidative stress modulation.

Table 1: Showing the different demographic profiles of the patients of both groups.

 Table 2: Showing the post-operative outcomes in Vitamin C versus placebo-treated patients.

The findings of this randomized controlled trial demonstrate that intravenous vitamin C administration significantly improves clinical outcomes in patients developing vasoplegic syndrome following cardiopulmonary bypass (CPB). Our results show three key benefits: a substantial reduction in vasopressor requirements, faster resolution of vasoplegic symptoms, and decreased intensive care unit (ICU) length of stay. These findings have important implications for the management of this common and challenging postoperative complication in cardiac surgery patients.

Pathophysiological Considerations:

The observed clinical benefits align closely with vitamin C's known physiological mechanisms of action. As an essential cofactor for dopamine β-hydroxylase in catecholamine biosynthesis, vitamin C plays a critical role in norepinephrine production. This biochemical relationship likely explains our finding of significantly reduced noradrenaline requirements in the treatment group (38.6% vs 68.2% requiring vasopressors, p=0.004). The vitamin's ability to potentiate endogenous catecholamine production may help overcome the adrenergic receptor desensitization that characterizes vasoplegic syndrome.

Beyond its role in catecholamine metabolism, vitamin C exerts multiple protective effects on vascular function. As the body's primary water-soluble antioxidant, it effectively scavenges reactive oxygen species generated during CPB, including superoxide anions and peroxynitrite [12]. This antioxidant activity helps preserve endothelial function by preventing oxidative inactivation of nitric oxide synthase while reducing harmful peroxynitrite formation. These mechanisms likely contributed to the significantly higher mean arterial pressures observed in our vitamin C group immediately post-CPB (93.2 vs 81.1 mmHg, p=0.035). Vitamin C's anti-inflammatory properties may represent a third important mechanism. Through inhibition of nuclear factor kappa-B (NF-κB) signaling, vitamin C reduces production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [13]. This modulation of the systemic inflammatory response to CPB may help explain the faster resolution of vasoplegia in our treatment group (14.4 vs 24.6 hours, p<0.001).

Our results extend findings from sepsis research to the specific context of CPB-induced vasoplegia. The reduced vasopressor requirements mirror results from the CITRIS-ALI trial in septic shock [14], while the shorter ICU stays are consistent with Marik's earlier sepsis study [15]. However, our mortality results (2.3% vs 4.5%, p=0.555) differ from some sepsis trials, possibly reflecting fundamental differences in the pathophysiology of sepsis versus CPB-induced inflammation. Several previous studies have examined vitamin C in cardiac surgery with mixed results. Our positive findings contrast with the negligible effects reported by Spoelstra-de Man et al. [16], but align with the reduced vasopressor requirements observed by Zabet et al. [11]. These discrepancies may relate to differences in dosing regimens, patient populations, or outcome measures. Our study improves upon previous work by employing a rigorous double-blind design, standardized dosing protocol, and comprehensive hemodynamic monitoring.

The clinical implications of our findings are substantial. Vasoplegic syndrome remains a significant cause of morbidity following cardiac surgery, with conventional vasopressor therapy carrying well-documented risks including arrhythmias, myocardial ischemia, and end-organ damage. Our demonstration that vitamin C can reduce vasopressor requirements by nearly 30% represents an important advance in managing this complication.

The 1.1-day reduction in ICU length of stay has both clinical and economic significance. For patients, this translates to decreased exposure to ICU-associated complications, including nosocomial infections and delirium. For healthcare systems, reduced ICU stays can substantially lower treatment costs while improving bed availability. Given vitamin C's excellent safety profile and low cost, these benefits could be achieved with minimal additional expense or risk. The temporal pattern of vitamin C's effects provides important clues about its mechanisms of action. The rapid improvement in mean arterial pressure following administration suggests immediate effects on vascular tone, possibly through modulation of nitric oxide bioavailability. The more gradual reduction in vasopressor requirements may reflect vitamin C's role in catecholamine synthesis, which would require time for new norepinephrine production and storage. Our finding that vitamin C accelerated vasoplegia resolution but did not significantly affect mortality parallels results from other studies of adjuvant vasoplegia treatments. This pattern suggests that while vitamin C improves hemodynamic parameters, its effects may not be sufficient to overcome all contributors to postoperative mortality in cardiac surgery patients. However, our study was not powered to detect mortality differences, and larger trials are needed to fully evaluate this outcome. Several limitations must be considered when interpreting our results. First, the single-center design may limit generalizability, though our patient population was representative of typical cardiac surgery cohorts. Second, while adequately powered for our primary endpoint, the sample size was insufficient to draw definitive conclusions about relatively rare outcomes like mortality.

Targeted therapies play a vital role in improving outcomes in post-cardiopulmonary bypass (CPB) vasoplegia. Among these, vitamin C has emerged as a promising adjunct, particularly in refractory cases. Its administration has been associated with enhanced patient outcomes, including reduced reliance on postoperative inotropic support (such as norepinephrine) to maintain a mean arterial pressure (MAP) above 65 mmHg, as well as shorter ICU stays. Nevertheless, larger randomized controlled trials are warranted to validate these findings and to define the optimal dosing strategy for vitamin C in this setting.

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