In our retrospective cohort study of critically ill patients, patients who received colistin with ascorbic acid as adjunctive therapy had similar odds of developing CIN compared to patients who received colistin only. We studied the effect of the low adjunctive dose of ascorbic acid in critically ill patients who received colistin, as it has been demonstrated in preclinical studies that ascorbic acid has a protective effect against the nephrotoxicity and tubular apoptosis caused by colistin.14,16 These studies revealed that ascorbic acid could reduce CIN due to its antioxidant properties.14,15 The main mechanisms of CIN are acute tubular necrosis, manifested as decreased creatinine clearance.16,17 and interstitial nephritis.18 However, CIN may be attributable to oxidative damage and inflammation.19
In this study, no significant difference was observed in the prevalence of CIN after propensity score matching, which was 35% in both groups; p-value = 0.6952. These results are consistent with results from a randomized clinical trial conducted on 28 patients; the study did not show any nephroprotection in the ascorbic acid group. 11 However, the nephroprotective effects of ascorbic acid could not be observed due to the small number of included patients in our analysis and utilization of a lower dose than in other trials (2-4 g of ascorbic acid daily).20,21 Higher ascorbic acid dosages or longer administration times may have produced different results. A prospective cohort study of critically ill patients with sepsis. 21; had comparable results with preclinical studies 14,15, which showed that ascorbic acid was an independent protective factor against AKI in patients treated with colistin. 21 The incidence rate of colistin-induced nephrotoxicity was reported in different trials to be in the range between 0 to 53.5%, 6 which is consistent with our study results. In addition, the mean age in our study is relatively low (45.5 ±17.74), nephrotoxicity has proven to occur more significantly in patients older than 60 years of age.21, 22
After statistical matching, all patients included in this study had similar baseline kidney function. Two patients (4.4%) in each group had chronic kidney disease. Similarly, analyzing the effect of nephrotoxic drugs; vancomycin, aminoglycosides, and contrast that were administered during colistin treatment could affect the results. However, after propensity score matching the baseline use of these drugs was not significant between groups. Concomitant use of vancomycin and aminoglycosides for two days or more were 83.3% and 44.4%, respectively. At the same time, the use of contrast during ICU stay was 57.8% (Table 1).
Among the 90 patients, we observed that 30-day mortality, in-hospital mortality, and hospital LOS were similar between the two groups. ascorbic acid has been studied in multiple randomized and observational studies in critically ill patients. A meta-analysis study was conducted to evaluate the effects of ascorbic acid administration on clinical outcomes. This meta-analysis included forty-four randomized trials in which 16 of them were performed in an ICU setting. Ascorbic acid administration was not associated with a difference in mortality, acute kidney injury, ICU, or hospital length of stay compared with control.23 In addition, the current sepsis guidelines 24 recommend against ascorbic acid supplementation in critically ill patients. This recommendation was based on an updated analysis that included nine RCTs. Ascorbic acid did not reduce mortality compared to usual care (RR, 0.9; 95% CI, 0.69−1.18). Further studies with higher quality may influence future updates by the guidelines. 24
Our study has the advantage of describing a cohort of critically ill patients treated by colistin with or without ascorbic acid to assess its role in nephroprotection. However, it has several limitations; first, it was a retrospective observational design with a small sample size that may contribute to the analysis and make it unable to detect the differences between groups. Second, it was conducted at a single center, limiting its generability. Third, the possibility of confounder; in our study, the patient's age, SOFA score, and serum creatinine were controlled by statistical matching. Last, the lower dose of ascorbic acid than the doses utilized in other trials might limit reaching a renal protective effect; higher ascorbic acid dosages or longer administration times may have produced different results. Therefore, the results of this study could be used to support the need for further large-scale studies with controlling the confounders to determine whether ascorbic acid has a role in the prevention of colistin-induced nephrotoxicity.