We included all RCTs conducted in patients with sepsis or septic shock aged 18 years or older. Results are reported according to the PRISMA extension for NMA (Supplement 1). The protocol was registered in PROSPERO (CRD42018103860) with the rationale for the study and detailed analysis methods published prior to data extraction and analysis. We conducted a systematic review with NMA and component NMA.
We aimed to assess whether vitamin C, glucocorticoids, and vitamin B1 alone or in combination improved patient outcomes by comparing the effect of different therapeutic regimens on mortality and other clinical outcomes in patients with sepsis or septic shock. Accordingly, we conducted a network meta-analysis (NMA) and component NMA to summarize the available evidence concerning these therapies and determine any incremental effect of each component when added to sepsis treatment. īecause a range of combinations of vitamin C, glucocorticoids, and vitamin B1 has been tested, the evidence-base for these treatments is complicated and cannot be summarized by a simple, conventional, pairwise meta-analysis.
Vitamin B1, an essential cofactor in cellular metabolism, is also depleted in patients with sepsis, and administration of vitamin B1 has been reported to reduce lactate levels in patients with sepsis. A recent systematic review and meta-analysis of RCTs suggested that low dose glucocorticoids do not reduce mortality but are associated with a shorter duration of artificial organ support. The role of glucocorticoids in sepsis or septic shock has also been extensively investigated. After a phase I study of vitamin C suggested dose-dependent improvement in vascular tone and attenuation of organ dysfunction, many randomized clinical trials (RCTs) evaluating this therapy have been undertaken. Vitamin C is depleted in patients with sepsis. Such metabolic resuscitation has generally involved a combination of vitamin C, glucocorticoids, and vitamin B1 or one of its components. Recently there has been considerable interest in “metabolic resuscitation” as adjunctive therapy for sepsis and septic shock. Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, − 29.8 h ) and ICU stay (incremental mean difference, − 1.3 days ). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. 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). Forty-three RCTs (10,257 patients) were eligible. 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). The primary outcome was longer-term mortality (90-days to 1-year). We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. 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. The final search was carried out on September 3rd, 2021. MEDLINE, Embase, CENTRAL, and WHO-ICTRP were searched. 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.
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