Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis

Abstract

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, − 29.8 h [95% CI − 44.1 to − 15.5]) and ICU stay (incremental mean difference, − 1.3 days [95% CI − 2.2 to − 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06558-0.

Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

“…However, the present results should be interpreted with caution because the difference of mortality was extremely small. The finding that vitamin C of ≥ 5 days was associated with an even greater decrease in mortality is consistent with previous meta-analysis suggesting that there may be a dose–response relationship between vitamin C and mortality [ 13 ]. Additional randomized trials evaluating very high-dose, long-term vitamin C for sepsis are warranted.…”

“…Conversely, the CITRIS-ALI trial tested a higher dose of vitamin C (200 mg/kg/day) and found a significant decrease in mortality among patients with sepsis and acute respiratory distress syndrome [ 7 ]. Interestingly, a recent meta-analysis revealed the associations between high-dose (≥ 6 to < 12 g/day) and very high-dose (≥ 12 g/day) vitamin C and decreased mortality [ 13 ].…”

“…These are in line with recent guidelines that advocate for the use of corticosteroids in septic shock [ 31 , 32 ]. However, it may be noted that several meta-analyses showed that vitamin C monotherapy was more beneficial than when administered in combination with corticosteroids [ 13 , 33 ]. Interestingly, the combination of vitamin C and thiamine was associated with a further lower mortality in certain subgroups, while other studies have not shown this finding [ 13 , 33 ].…”

“…However, it may be noted that several meta-analyses showed that vitamin C monotherapy was more beneficial than when administered in combination with corticosteroids [ 13 , 33 ]. Interestingly, the combination of vitamin C and thiamine was associated with a further lower mortality in certain subgroups, while other studies have not shown this finding [ 13 , 33 ]. Additional studies are required to determine potential optimized drug combinations.…”

“…Low-dose corticosteroids have been shown to reverse septic shock [ 11 , 12 ], although the use of hydrocortisone was not controlled in most of these trials [ 7 , 9 , 10 ]. A recent network meta-analysis evaluated larger samples to estimate the effect of vitamin C, corticosteroids, and thiamine alone or in combination on mortality and other outcomes [ 13 ]. However, this analysis did not assess the treatment duration and may be limited by heterogeneity of the published studies.…”