In the previous five decades sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The sepsis characterization was described by four systemic inflammatory response syndrome (SIRS) criteria consisting of tachycardia; tachypnea; fever or hypothermia; and leukocytosis, leukopenia or bandemia (1).
Severe sepsis was defined as sepsis complicated by organ dysfunction, which could progress to septic shock, defined as “sepsis-induced hypotension persisting despite adequate fluid resuscitation. The sepsis description expanded the list of diagnostic criteria, including a set of 24 general, inflammatory, hemodynamic, organ dysfunction or tissue perfusion parameters. In the sepsis-2 definition the criteria for severe sepsis stayed alike, whereas septic shock was defined more clearly as refractory hypotension even with sufficient fluid resuscitation (2). The 2016 Task Force also introduced the quick sequential organ failure assessment (SOFA), or qSOFA, score, composed of three components that are easy to measure at the bedside: respiratory rate of 22 breaths/min or greater, altered mentation and systolic blood pressure of 100 mm Hg or less. Evidence indicated that in out-of-hospital, emergency department and general hospital ward settings, adult patients with suspected infection and a higher risk for poor outcomes typical of sepsis can be rapidly identified by the presence of at least two qSOFA criteria. The rapid assessment tool such as SOFA was presented to grade sepsis severity and predicts in-hospital mortality based on well-defined multi-physiological criteria (3).
 In the past 2 decades, numerous studies have suggested that the incidence of sepsis is increasing over time, while mortality is decreasing and sepsis is considered as a serious public health problem. The steady decrease of sepsis-related mortality over time most likely reflects the overall improvement in ICU practice in the last 20 to 30 years. This is supported by the finding from the above-mentioned Australian and New Zealand ICU registry study which the observed annual reduction in mortality did not differ between patients with severe sepsis and other diagnoses. Key factors that contribute to the overall rise in the worldwide incidence of sepsis include the aging of the population, the emergence of antimicrobial resistance, the growing use of immunosuppressive drugs and therapies and the increased number of patients who are at risk for developing sepsis. In high-income countries, a global estimation of 31.5 million sepsis cases, with potentially 5.3 million annually deaths were reported (4). Due to the high prevalence of infectious disease such as malaria, HIV and dengue fever, sepsis is considered to be a substantial problem of out-hospital deaths in low-income countries (5, 6). Although mortality rate has diminished from 1990 to 2017 by 52.8% and the reported 11.0 million sepsis-related deaths annually still account for 19.7% of the total deaths (7).
Kim et al. showed that intravenous injection of vitamin C reduced lipid peroxidation and oxidative stress, which leads to the expression of the gene regulating liver vessels in polymicrobial sepsis, and in this way, the vitamin reduced liver micro vascular dysfunction in the course of sepsis in rats (8). Regarding endothelial dysfunction in SIRS, various clinical studies have been conducted on the beneficial effects of vitamin C in endothelial cells, especially in chronic stress conditions, which the results demonstrated improvement the function of endothelial cells in either insulin-dependent (9) or  independent (10) diabetic patients  with chronic hypertension (11). In these studies, vitamin C was administered intra-arterially or intravenously and the increased nitric oxide (NO) was suggested to the possibility of its protective effects against destruction by reactive oxygen species (ROS). The importance of the effect of NO on endothelial function is its role as a vasodilator and inhibition of platelet aggregation (12).
Lack of NO is pathological due to the effect on vascular endothelium and loss of micro vascular circulation (13, 14) on the other hand, high concentration of NO leads to increased vascular permeability in SIRS (15). Inducible nitric oxide synthase (iNOS) or neuronal nitric oxide synthase (nNOS) appear to facilitate sepsis-induced damage but endothelial nitric oxide synthase (eNOS) has protective effects in this case (16). It is important to know that iNOS expression leads to inflammation in almost all major cells of the body while eNOS is expressed by endothelial cells. Administration of vitamin C decreases iNOS (17, 18) but increases eNOS (19).
In addition to NO dysregulation, other endothelial cell changes such as endothelial cell apoptosis, up regulation of adhesion molecules, and pro-coagulant state (20) occur during SIRS and vitamin C seems to be effective in correcting these factors (19, 21-23). It has been found that in vitro vitamin C in human umbilical vein endothelial cells (HUVEC) in response to TNF-alpha reduces the expression of the endothelial cell adhesion molecule ICAM-1 (24) and leads to the suppression of neutrophil systemic discharge during sepsis, especially in the lung (25). Among the other beneficial effects of vitamin C in endothelial cells is the suppression of tissue factor production and regulation of response to inflammatory stimuli (26) and prevents excessive coagulation and vitamin C supplementation reduces the permeability and activation of fluids from the endothelium (27-29). The results of clinical studies have shown that different ways of administering vitamin C have different effects. So that the oral vitamin C supplement probably has relatively minor effects due to limited absorption and the maximum absorption of vitamin C is obtained with a dose of 200 mg (30). Higher doses cause diarrhea and abdominal cramps due to the effects of ascorbate accumulation in the intestinal lumen (31) which is why parenteral administration has been used in various studies. In a sample of studies, intravenous but not oral administration resulted in increased endothelial responsiveness (32).
In patients with both sepsis and septic shock, a combination therapy of hydrocortisone, vitamin C, and thiamine, compared with placebo, could diminish the duration of vasopressor use and SOFA scores during the first 72 h (33), moreover, it has been shown that destructive consequences of sepsis are reduced by vitamin C infusion in mice (34). It seems that vitamin C has a positive effect on the rate of organ failure and inflammatory responses and endothelial damage in patients with severe sepsis (35). Administration a diet containing vitamin C led to an improvement in the prognosis in the sepsis rat model by reducing inflammatory damage (36). The combined treatment of hydrocortisone, intravenous vitamin C and thiamine led to strengthening the immune system and organ damage and reduced the risk of death and organ failure following sepsis (37-41), however, in patients with septic shock, there was no change or slight improvement in the clinical relationship of health-related quality of life in people receiving combined treatment with vitamin C, corticosteroids and thiamine compared to placebo (42-46).
Because of the above mentioned discrepancies about vitamin C effects in sepsis, in the present study we evaluated the prognosis of the patients with sepsis who were admitted in Zanjan Vali-asr hospital with history of vitamin C administration in Feburary 2019 to June 2020.
 

In the present experiment totally 54 patients; (26 pationts which were received vitamin C, 25 mg/kg, IV, daily for four days) and (28 people without vitamin C reception) have been compared.
There were no statistical differences between demographic data in the beginning of evaluation: gender (p= 0.513), age (P= 0.569), background disease (P= 1), history of drugs (medicines) usage (P= 0.571), origin of sepsis (P= 1) and early complication of sepsis (P= 0.722) between the two groups (Table 1).
 
Table 1. Demographic data of patients in two groups were received vitamin C as test group (25 mg/kg, IV, daily for four days) and 28 people without vitamin C as control group. Vit. C: group which received vitamin C In the beginning of evaluation.

After four days of assessment, the evaluated clinical complications: Loss of consciousness (P= 1), septic shock (P= 0.596) and respiratory failure (P= 0.237) were not altered (Table 2).

 
Table 2. Clinical complications in two groups were received vitamin C as test group (25 mg/kg, IV, daily for four days) and 28 people without vitamin C as control group. Vit. C: group which received vitamin C for 4 days.

After four days of evaluation, measured laboratory scales were not different: WBC (p=0.394), Hb (P=0.97), Platelet (P=0.524), BUN (P= 0.174), Cr (P= 0.149), BS (p=0.951), Na (P=0.184), K (P=0.371), ALT (P= 0.194), AST (P= 0.452), ALP (p=0.182), Ca (P=0.691), ESR (P=0.56), CRP (P= 0.591), Bilirubin-total (P= 0.719), Bilirubin-D (p=0.536), PT (P=0.562), INR (P=0.477), U/A (P= 0.612), U/C (P= 0.237) and B/C (P= 1) between two groups (Table 3).

 
Table 3. Some laboratory scales in two groups were received vitamin C as test group (25 mg/kg, IV, daily for four days) and 28 people without vitamin C as control group. Vit. C: group which received vitamin C for 4 days.

Either mean days hospitalization in ICU (p= 0.919) or Sofa score (P= 0.711) were not changed after four days of evaluation (Table 4).

Discussion

Sepsis was defined as (documented or suspected) infection leading to the onset of SIRS as reflected by the presence of two or more SIRS criteria. Septic shock is defined as a subcategory of sepsis patients followed by circulatory and cellular/metabolic dysfunction (3). There is information which has been showed no change or modest improvement and questionable in clinical relevance in the health-related quality of life in patients with septic shock treated with vitamin C alone or in combination compared to placebo (42-46).
In the beginning the demographic data [gender, age, background disease, history of drugs (medicines) use, origin of sepsis and early complication of sepsis] were evaluated. They were not statistically different which indicated that two groups have been matched.
There were no statistical differences between some laboratory scales (WBC, Hb, Platelet, BUN, Cr, BS, Na, K, ALT, AST, ALP, Ca, ESR, CRP, Bilirubin-total, Bilirubin-D, PT, INR, U/A, U/C and B/C) after four days of evaluation between test and control groups. Iglesias et al. has shown these results too moreover the same results have been illustrated by Litwak and his colleagues (40 and 47).
Our data indicated that the mean days hospitalization in ICU was not different in two groups. A meta-analysis from 10 studies (4 randomized controlled trials [RCTs] and 6 retrospective studies) which involving 1671 patients (495 in the vitamin C treatment group and 1176 in the control group) disclosed that the use of vitamin C did not reduce the length of ICU or hospital stay (48). Moreover, Zabet et al., indicated that vitamin C administration showed no effect on hospital duration stay (49), Mitchell et al., study revealed that the hospital length of stay did not changed by vitamin C administration after 12 and 24-month follow-up (50). Fowler et al. indicated this result by a randomized, double-blind, placebo-controlled, multicenter trial which conducted in seven medical intensive care units in the United States, enrolling patients (N = 167) with sepsis (51).
At last Sofa score was assessed which no statistical differences between two groups have been seen after four days of evaluation. The same results have been demonstrated by other investigations. Iglesias et al. demonstrated no significant differences in SOFA score in a combination therapy of IV vitamin C, thiamine and hydrocortisone in 137 patients were randomized to the treatment (n = 68) and control group (n = 69) (48). Fowler et al. showed reduced sofa score in twenty four randomized patients with severe sepsis in intensive care unit whom received intravenous infusions every six hours for four days of vitamin C (35).
Moreover, a randomized trial in 205 patients (103 with intervention and 102 with placebo group) treated with combination parenteral vitamin C (1500 mg), hydrocortisone (50 mg) plus thiamine (100 mg) every 6 hours for 4 days versus placebo in matching volumes at the same time points did not reduced sofa csore (52). Weilan et al. proved by nine RCTs, enrolling 1427 patients of sepsis and septic shock treated with vitamin C, hydrocortisone plus thiamine (717) or only standard care (710) that this combination therapy slightly improved the SOFA score in the first 72 h in patients with sepsis (53).
Rosengrave et al. did not found a significant decreases in the sofa score by a double-blind, randomized placebo-controlled trial in 40 patients with septic shock who receive intravenous vitamin C (at a dose of 25 mg/kg every 6 h) or placebo (intravenous 5% dextrose) (54).
A systematic review and meta-analysis of 20 randomized clinical trials (2124 participants) showed that vitamin C alone or combined with thiamine and/or hydrocortisone, compared to placebo, standard care or hydrocortisone showed a little to no difference or very uncertain evidence for SOFA score improvement (53) but a meta-analysis conducted by Wu et al. which consists six randomized controlled trials (RCTs) and seven observational studies enrolling 1,559 patients were included (762 were treated with combination therapy of hydrocortisone, vitamin C, and thiamine, and 797 were treated with hydrocortisone alone, standard care or placebo) in patients with sepsis and septic shock, showed a reduction in the SOFA scores during the first 72 h (33).

 

Conclusion

Our finding demonstrated that there were no significant differences between control and vitamin C received groups nonetheless for precise conclusions more studies with a larger groups are required.

 

Acknowledgements

None.

 

Conflicts of Interest

The authors declare no conflict of interest.

 

Funding

 None Declared.