Vitamin C administration in the critically ill: a summary of recent meta-analyses

Since 2018, there has been a dramatic upsurge in publications relating to the use of vitamin C in critically ill patients, particularly those suffering from sepsis [1]. This has primarily been in response to the well-publicized before-and-after study of Marik et al. [2], which indicated that intravenous administration of 6 g/day vitamin C (in combination with thiamine and hydrocortisone) could improve the outcomes of patients with sepsis, including decreasing mortality. Over the past year, seven meta-analyses assessing the effects of vitamin C administration in critically ill patients have been published, with four appearing in the past 4 months alone (see Table 1 summary).

Table 1 A summary of recent meta-analysis of vitamin C administration in critical care patients

The most recently published and largest meta-analysis included 44 randomized controlled trials (16 intensive care and 28 cardiac surgery) [9]. Although meta-analyses that include a larger number of studies have increased power, they run the risk of comparing disparate studies. This is particularly the case with vitamin C studies whereby the dose (milligrams vs grams), rout of administration (oral vs intravenous), duration (hours vs days), and disease (e.g., sepsis vs cardiac surgery) can have a large impact on outcomes [10, 11]. Therefore, appropriate subgroup analyses should be carried out, although this is currently challenging due to the low number of comparable studies.

All but one of the current meta-analyses have focused on mortality as a primary outcome, despite many of the included trials having relatively low numbers of patients. In most cases, no effect of intervention was observed on mortality, except in specific subgroup analyses (e.g., sepsis and higher dose intravenous vitamin C). However, there have been few of these studies published to date, and even fewer of high methodological quality [6]. Other commonly assessed outcomes included ICU and hospital length of stay, duration of vasopressor support and mechanical ventilation, and acute kidney injury. Some of the meta-analyses showed decreases in several of these secondary outcomes, while others showed no effect, depending on the selection criteria used for study inclusion (Table 1).

There are currently over a dozen randomized controlled trials registered on clinicaltrials.gov that are assessing the effects of vitamin C administration in critically ill patients, particularly those with sepsis. One would hope that in the short term, no more meta-analyses appear every time another small study is published, but instead wait until some of the larger trials (such as VICTAS and LOVIT) have been completed. Otherwise, there may end up with more meta-analyses than published trials.