The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials
Authors: Juan Carlos Lopez-Delgado
Giovanni Landoni
Anne-Marie Daems
Alessandro Putzu
Vito Federico Giordano
Journal: Critical Care Medicine (2019)
Discipline: CLINICAL MEDICINE
Keywords: vitamin C; critically ill patients; randomized controlled trials; mortality; postoperative atrial fibrillation
Affiliations: Division of Anesthesiology, Department of Anesthesiology, Pharmacology & Intensive Care Medicine, Geneva University Hospitals, Geneva, Switzerland., Intensive Care Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain., Institut d'Investigació Biomèdica Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy., Vita-Salute San Raffaele University, Milan, Italy.

Abstract:  Objectives: The effects of vitamin C administration on clinical outcome in critically ill patients remain controversial. Data sources: Online databases were searched up to October 1, 2018. Study selection: We included randomized controlled trials on the use of vitamin C (any regimen) in adult critically ill patients versus placebo or no therapy. Data extraction: Risk ratio for dichotomous outcome and standardized mean difference for continuous outcome with 95% CI were calculated using random-effects model meta-analysis. Data synthesis: Forty-four randomized studies, 16 performed in ICU setting (2,857 patients) and 28 in cardiac surgery (3,598 patients), published between 1995 and 2018, were included in the analysis. In ICU patients, vitamin C administration was not associated with a difference in mortality (risk ratio, 0.90; 95% CI, 0.74-1.10; p = 0.31), acute kidney injury, ICU or hospital length of stay compared with control. In cardiac surgery, vitamin C was associated to a reduction in postoperative atrial fibrillation (risk ratio, 0.64; 95% CI, 0.52-0.78; p &lt; 0.0001), ICU stay (standardized mean difference, -0.28 d; 95% CI, -0.43 to -0.13 d; p = 0.0003), and hospital stay (standardized mean difference, -0.30 d; 95% CI, -0.49 to -0.10 d; p = 0.002). Furthermore, no differences in postoperative mortality, acute kidney injury, stroke, and ventricular arrhythmia were found. Conclusions: In a mixed population of ICU patients, vitamin C administration is associated with no significant effect on survival, length of ICU or hospital stay. In cardiac surgery, beneficial effects on postoperative atrial fibrillation, ICU or hospital length of stay remain unclear. However, the quality and quantity of evidence is still insufficient to draw firm conclusions, not supporting neither discouraging the systematic administration of vitamin C in these populations. Vitamin C remains an attractive intervention for future investigations aimed to improve clinical outcome. 

Retracted: No

PubPeer comments:
 # Statistical problems in a meta-analysis on vitamin C and critically ill patients An important goal in modern biomedicine is specificity. The strength of the RCT is that the difference between the trial groups can be specifically attributed to the intervention that is being tested. The title of a recent review in Critical Care Medicine by Putzu et al. indicated that their focus was the specific effect of vitamin C for critically ill patients (1). The abstract describes that they *u201cincluded randomized controlled trials on the use of vitamin C (any regimen) in adult critically ill patients versus placebo or no therapyu201d*, though the reader does not know what the u201cany regimenu201d means in the context. However, Table 1 of the review shows that only five of the 16 included ICU trials were vitamin C trials. Eleven of the included ICU trials administered vitamin C together with vitamins A, B, or E, or with selenium, zinc, etc. Thus, those 11 trials do not test the specific effect of vitamin C on ICU patients. The other substances can have negative or positive effects of their own, biasing the analysis of vitamin C effects. In the field of meta-analysis, combining results of trials which are too different, is referred to as the apples and oranges problem. The Putzu et al. meta-analyses (1) estimated the effect of vitamin C on continuous outcomes by using the standardized mean difference (SMD) scale, which uses the standard deviation (SD) as the unit of the scale. In their abstract, Putzu et al. stated erroneously that in cardiac surgery patients vitamin C decreased the length of ICU stay by 0.28 days (1), whereas the correct statement is that ICU stay was reduced by 0.28 SD units. However, the unit of SD is incomprehensible to most readers. The Cochrane Handbook, for example, discourages use of the SMD scale: *u201cu2026 the method assumes that the differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study populations. This assumption may be problematic in some circumstances where we expect real differences in variability between the participants in different studiesu2026 The overall intervention effect can also be difficult to interpret as it is reported in units of standard deviation rather than in units of any of the measurement scales used in the reviewu201d* (2: sect 9.2.3.2). Putzu et al. also included some trials twice. In subgroup analysis 2.1.2 of eFigure 8, Putzu includes both the Sadeghpour (3) and the Moludi (4) trials. Both were carried out at Rajaie Cardiovascular Medical and Research Center at Iran University of Medical Sciences. Both had 290 patients, with 113 vitamin C participants and 177 control participants, and with 191 men and 99 women (3,4). In both reports the duration of intubation was 11.8 hours in the vitamin C group and 14.14 hours in the control group, and in both the incidence of post-operative atrial fibrillation was 35% in the vitamin C group and 55% in the control group (3,4). There are two authors in common for both trial reports and it seems evident that the Moludi (4) report is a Farsi translation of the English report by Sadeghpour (3). Thus, Putzu counted the same trial twice. In subgroup analysis 2.4.2 of eFigure 9, Putzu includes both the Alshafey (5) and the Retz (6) trials. Putzu does not give a reference to either trial in their reference list (1). However, eTable 6 indicates that both trials were published in u201cJournal of the Egyptian Society of Cardio-Thoracic Surgeryu201d, though the author of the latter trial is written as Rezk in eTable 6. Search of that journal identifies the Alshafey (5) trial but no separate Retz Rezk (6) trial. The only vitamin C paper in that journal by Rezk as an author is the Alshafey (5) trial where Rezk is a co-author. Furthermore, in the subgroup analysis both trials have 50 participants in the vitamin C and placebo groups. In both trials the length of ICU stay was 2.78 days in the vitamin C group and 3.58 days in the control group with identical SD values. Evidently, a single trial is also included twice in this case. It is common for results from a trial to be reported in separate forums, however a trial should only be included once in a meta-analysis. For example, the Cochrane Handbook instructs: *u201cStudies are frequently reported in more than one publication (Tramu00e8r 1997, von Elm 2004). However, the unit of interest in a Cochrane Intervention review is the study and not the report. Thus, information from multiple reports needs to be collatedu201d*(2: sect 7.6.4). It seems that Putzu et al. did not follow such guidance. We undertook our own meta-analysis of vitamin C for critically ill patients and found 17 controlled trials that were informative about the specific effect of vitamin C on the length of ICU stay (7). Restricting our analysis to 12 trials with 1766 patients, we calculated that vitamin C reduced the length of ICU stay by 7.8% (p = 0.00003). We calculated the effect of vitamin C on the relative scale, since there is strong evidence that the relative scale better captures the effects on duration (7,8,9). In their abstract, Putzu et al. write that *u201cin a mixed population of ICU patients, vitamin C administration is associated with no significant effect on u2026 length of ICU or hospital stayu201d* (1). However, our review shows that restricting the analysis to trials of vitamin C alone, carrying out the search thoroughly, and using the relative scale can lead to very different conclusions about the effects of vitamin C on the length of ICU stay (7). **References** 1.tPutzu A, Daems AM, Lopez-Delgado JC, Giordano VF, Landoni G. The effect of vitamin C on clinical outcome in critically ill patients: a systematic review with meta-analysis of randomized controlled trials. Crit Care Med 2019;47:774u201383. https: doi.org 10.1097 CCM.0000000000003700 2.tCochrane Handbook. Sections 7.6.4 and 9.2.3.2. http: handbook-5-1.cochrane.org 3.tSadeghpour A, Alizadehasl A, Kyavar M, et al. Impact of vitamin C supplementation on post-cardiac surgery ICU and hospital length of stay. Anesth Pain Med 2015;5:e25337. https: www.ncbi.nlm.nih.gov pmc articles PMC4350190 4.tMoludi J, Keshavarz S, Pakzad R, et al. Effect of vitamin C supplementation in the prevention of atrial fibrillation. Tehran Univ Med J 2016;73:791u20137. http: tumj.tums.ac.ir article-1-7191-en.html 5.tAlshafey MK, Elrakhawy HM, Rezk ME, Moustafa HM. Role of ascorbic acid in reduction of the incidence of the atrial fibrillation in patients under beta-blocker and undergoing coronary artery bypass graft operation in early post-operative period. J Egyptian Soc Cardio-Thoracic Surgery 2017;25:198-203. https: doi.org 10.1016 j.jescts.2017.04.003 6.tRetz (cited in 2.4.2 of eFigure 9 of ref 1. without any details of the reference; apparently a duplicate of ref. 5). 7.tHemilu00e4 H, Chalker E. Vitamin C can shorten the length of stay in the ICU: a meta-analysis. Nutrients 2019;11:708. https: doi.org 10.3390 nu11040708 8.tFriedrich, JO, Adhikari NK, Beyene J. Ratio of means for analyzing continuous outcomes in meta-analysis performed as well as mean difference methods. J Clin Epidemiol 2011;64:556u201364. https: doi.org 10.1016 j.jclinepi.2010.09.016 9.tHemilu00e4 H. Duration of the common cold and similar continuous outcomes should be analyzed on the relative scale: a case study of two zinc lozenge trials. BMC Med Res Methodol 2017;17:82. https: doi.org 10.1186 s12874-017-0356-y , 
 Firstly, we would like to thank Dr. Harri Hemilu00e4 for the comments and criticisms on our study (1). We did include a large amount of data in the supplementary material to improve transparency and allow a full assessment of our study. We decided to perform a large comprehensive meta-analysis on vitamin C supplementation in different settings; as we anticipated a low number of studies administering only vitamin C, we chose to include those studies administering vitamin C in combination with other drugs as well. All analyses are stratified by setting (ICU or cardiac surgery); no aggregate results are presented. We performed several subgroup analyses to evaluate any possible subgroup effects that would merit further investigation (e.g.; route of administration, vitamin C only administration). All these points are clearly stated in the manuscript. Inclusion and exclusion criteria of the meta-analysis are clearly reported in the full-text article. In the abstract we summarized in one paragraph the methods of our meta-analysis. It is rather obvious that to report all details in the abstract is impossible. The Sadeghpour trial (2) and the Moludi trial (3) had different inclusion criteria (mixed surgery vs. CABG only) and the Sadeghpour trial was submitted for publication (November, 14th 2014) before the end of the Moludi trial (March 2015). The endpoints of the studies were also different (Sadeghpour trial: length of hospital and ICU stay; Moludi trial: postoperative atrial fibrillation). Furthermore, as reported in our study, we had contacted the corresponding authors. We asked Moludi for an English version of his trial, without any reply to this specific question (we did receive mortality data, as reported in the supplement). We decided to include the two trials as separate studies. However, the similarities in some outcomes do raise some question on the quality of these trials, which were both evaluated to be at high risk of bias in our study. Indeed, the Alshafey and the Retz trials are the same study (4) and they were erroneously included in the meta-analysis on supraventricular arrhythmias and length of intensive care unit stay as different studies. We therefore thank you for this helpful comment. We performed the meta-analysis without the u201cRetz trialu201d and the results did not change. Length of ICU stay in cardiac surgery: sMD -0.28 [-0.43, -0.13] vs. sMD -0.25 [-0.39, -0.10] Supraventricular arrhythmias in cardiac surgery: RR 0.64 [0.52, 0.78] vs. RR 0.64 [0.53, 0.79] Thank you also for the comment on standardized mean difference. We fully agree that the u201cdu201d should be removed from length of ICU hospital stay outcomes. When analyzing the whole dataset with mean difference (MD), an easier to understand outcome estimate the results are similar for magnitude and direction: Length of ICU stay in cardiac surgery: sMD -0.25 [-0.39, -0.10] vs. MD -0.22 [-0.34, -0.09] (u201cRetz trialu201d excluded); Length of hospital stay in cardiac surgery: sMD -0.30 [-0.49, -0.10] vs. MD -0.85 [-1.38, -0.32]; Length of ICU stay in ICU trials: sMD 0.02 [-0.25, 0.29] vs. MD 0.06 [-1.80, 1.92]; Length of hospital stay in ICU trials: sMD -0.20 [-0.41, 0.01] vs. MD -2.00 [-4.32, 0.33]. We read with great interest the review of Dr. Harri Hemilu00e4 and Dr. Elizabeth Chalker (5). They included 13 trials on cardiac surgery, 2 on lung contusion, 1 on burns, 2 on sepsis. Our meta-analysis included 16 ICU trials and 27 cardiac surgery trials. Several major differences are present, such that the 2 meta-analyses significantly different. One of the main differences to be addressed is that we considered as very important some crucial points of cardiac surgery trials: the risk of bias of included trials, the clinical and statistical heterogeneity, the substantial differences between trials from USA Europe and other countries, and publication bias. According to these limitations, the small improvement in length of hospital and ICU stay reported by our and Hemilu00e4u2019s meta-analyses should be interpreted with caution in our opinion. Several randomized trials are ongoing and will elucidate the role of this drug on clinical outcome. We would like to point out that our study featured protocol registration, PRISMA checklist, reporting if the analyses were predefined or not, explicit search strategy, subgroup analyses according to risk of bias as suggested by Cochrane guidelines, and publication bias assessment. In conclusion, we would like to thank Dr. Harri Hemilu00e4 for his constructive comments: we should have removed a u201cdu201d from the manuscript and we have included one trial twice in the supraventricular arrhythmias and length of ICU stay meta-analysis in the subsetting of cardiac surgery. Luckily, the results of our meta-analyses are unchanged and this meta-analysis represent the best available evidence based medicine on vitamin C supplementation in critically ill patients. Prof. Giovanni Landoni, MD; Dr. Alessandro Putzu, MD. , 
 #2 Drs. Landoni and Putzu write about the Sadeghpour and Moludi trials: u201cThe endpoints of the studies were also different (Sadeghpour trial: length of hospital and ICU stay; Moludi trial: postoperative atrial fibrillation)u201d. However, this is not correct. Moludi et al write in their Abstract: u201cthe two groups were compared in terms of the following: Atrial and ventricular arrhythmias after surgery, ICU stay and hospital stay and duration of intubation.u201d http: tumj.tums.ac.ir article-1-7191-en.html Sadeghpour et al. write in their Methods: u201cAll the patients were monitored in the open heart ICU before their transfer to a ward. Data such as bypass time and cross-clamp time were collected intraoperatively. Additionally, information was gathered in the ICU on the total length of ICU stay, intubation time, drainage volume and presence of some complications (mortality and morbidity) defined as death, any infection, any impairment in the renal function and need for reoperation. Finally, the total duration of hospital stay was recorded for every individual.u201d In the Results section, they also report u201cthe overall incidence rate of postoperative AF [atrial fibrillation]u201d which means that they collected data also for that specific outcome. https: www.ncbi.nlm.nih.gov pmc articles PMC4350190 It is misleading to claim that the endpoints of the studies were different. They were extensively overlapping. Furthemore, Drs. Landoni and Putzu do not have any kinds of proposals how two independent studies might have identical numbers of males and females, and vitamin C and placebo participants, and identical duration of intubation in the study groups, and identical incidence of post-operative AF in the study groups. Such extensive identity in the figures makes it most likely that the Moludi reports is simply a Farsi translation of the Sadeghpour reports, as I proposed. Drs. Landoni and Putzu also write that u201cas we anticipated a low number of studies administering only vitamin C, we chose to include those studies administering vitamin C in combination with other drugs as well.u201d Multi-substance treatments can be investigated. However, we cannot draw a conclusion that the effect of a multi-substance intervention is caused by vitamin C specifically. Claiming that u201cstudies administering vitamin C in combination with other drugsu201d informs us about specific effects of vitamin C misleads the readers. ,