Iv Vitamin C For Sepsis

Sepsis is a dysregulated inflammatory response to an infection and remains a significant public health burden worldwide (¹). Early administration of antimicrobial agents, source control, and hemodynamic stabilization with fluid administration and vasopressors remain cornerstones of current sepsis treatment (²). Despite significant advances in the understanding of the pathophysiology of sepsis, no other treatment has been proven to improve mortality.

Vitamin C is an essential vitamin that cannot be synthesized by the human body. It is a potent antioxidant as well as an enzyme cofactor for a number of biosynthetic enzymes, including metalloenzymes, which synthesize intrinsic norepinephrine and vasopressin (³). Based on these functions, vitamin C has been implicated as a possible therapy to ameliorate the pathophysiology of sepsis. A previous randomized controlled trial (RCT) suggested that IV high-dose vitamin C, compared with IV low-dose vitamin C and placebo, improved the Sequential Organ Failure Assessment (SOFA) score in patients with sepsis (⁴). This study suggested a potential effect of vitamin C on the prevention of multiple organ failure that is likely to improve mortality, especially among high-risk patients with higher SOFA scores. Since then, more attention has been paid to high-dose vitamin C as a potential adjunct therapy for sepsis. Marik et al (⁵) reported significant improvement in the survival of patients with sepsis who received the combination therapy of hydrocortisone, vitamin C (ascorbic acid), and thiamine (HAT therapy) in 2017. Because this study was a relatively small retrospective before-and-after study, several RCTs have been conducted to verify this result. The previous meta-analysis reported favorable outcomes in the vitamin C group (⁶) although sample sizes of these studies were limited. Although newer meta-analyses were recently published (⁷ ^, ⁸), these studies did not include a recent larger RCT (⁹) and concluded that further studies with a larger number of patients are needed to provide further evidence. Given the lack of consensus on this theme, it is important to summarize the currently available evidence regarding the effect of IV high-dose vitamin C in patients with sepsis.

The aim of this study was to conduct a systematic review and meta-analysis of RCTs to investigate the effect of vitamin C therapy on the mortality of patients with sepsis.

METHODS

Protocol Registration

This study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (¹⁰). The protocol of this meta-analysis was registered in the University hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp) on May 26, 2020 (identification number: UMIN000040528).

Search Strategy

We comprehensively searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE on February 25, 2021. The search strategy included the following keywords: vitamin C, ascorbic acid, sepsis, systemic inflammatory response syndrome, and multiple organ failure. The search strategy is shown in Table S1 (https://links.lww.com/CCM/G746).

Study Selection and Inclusion Criteria

EndNote (Thomson Reuters, Toronto, ON, Canada) was used to store citations and remove duplicates. Two authors (R.S., D.H.) independently evaluated the abstracts and titles for those that fit the inclusion criteria. The full texts were retrieved and reviewed on Rayyan (¹¹). We only included articles published in English and excluded conference proceedings. When there were disagreements between the two reviewers, it was discussed in detail until a consensus was reached. The corresponding authors of articles that were included in this study were contacted to verify unclear information when necessary.

Trials were included based on the following criteria:

1) Study type: RCT.
2) Patient population: Patients greater than or equal to 18 years old with sepsis based on Sepsis-1 (¹²), Sepsis-2 (¹³), or Sepsis-3 definitions (¹⁴).
3) Intervention: IV high-dose vitamin C (≥ 1.5 g every 6 hr or 25 mg/kg every 6 hr).
4) Control: placebo or no intervention.

Data Extraction

Two authors (R.S., D.H.) independently extracted the data using a standardized form for data extraction. When multiple similar publications reported by the same investigators' group were detected, both authors carefully evaluated these publications and contacted the investigators to ensure that duplicate data were not included. The following information was collected: lead author's name, year of publication, country, the definition of sepsis, patient characteristics such as age, sex, SOFA score, sources of infection, inclusion and exclusion criteria, and follow-up duration.

The primary outcome was short-term mortality, which was defined as 28-day mortality, 30-day mortality, or in-hospital mortality, depending on the availability of the data. The secondary outcomes were short-term mortality based on the severity of sepsis (control SOFA score ≥ the median of included studies vs < the median of included studies), the type of intervention (HAT therapy vs non-HAT therapy), vasopressor duration, ventilator-free days, ICU length of stay (LOS), hospital LOS, delta SOFA score at 72–96 hours, and adverse events.

Risk of Bias Assessment

Two authors (R.S., D.H.) independently evaluated the methodological quality of the studies to determine the risk of bias. Further discussion was held in the event of any disagreement, and a third reviewer (N.P.) reviewed the full article and participated in a discussion when needed. This was continued until a consensus was reached. To evaluate the risk of bias of each trial, the Cochrane Collaboration's tool was used for assessing the risk of bias in each randomized trial (¹⁵ ^, ¹⁶).

Statistical Analysis

We performed analyses using the Mantel-Haenszel (M-H) random-effects models and inverse variance random-effects models for binary and continuous outcomes, respectively. Risk ratio (RR) or standardized mean difference (SMD) was reported as point estimates with 95% CIs and p values. For the data shown as medians and interquartile ranges (IQRs), medians and IQRs were converted to means and sds (¹⁷) to obtain pooled RRs and SMDs. All RRs were reported as the risk of short-term mortality for the intervention group in comparison with that of the control group. The M-H chi-square test and the I ² statistic were used to examine statistical heterogeneity (¹⁸). Substantial heterogeneity was predefined as a p value of less than 0.10 with the M-H chi-square test or an I ² statistic of greater than 50%.

A subgroup analysis was performed focusing on the severity of sepsis (control SOFA score ≥ the median of included studies vs < the median of included studies) and the type of intervention (HAT therapy vs non-HAT therapy).

We conducted a sensitivity analysis to investigate the robustness of the main result, analyzing a subgroup based on the study design (double-blind vs nondouble-blind RCT, and single-center vs multicenter RCT), and whether the dose of vitamin C was higher dose or lower dose. In this analysis, higher dose was defined as a vitamin C dose of greater than or equal to 25 mg/kg every 6 hours, and lower dose was defined as a vitamin C dose of 1.5 g every 6 hours or equivalent. To examine publication bias, we reported funnel plots for the primary outcome and tested the symmetry of the funnel plots using both Begg's test for rank correlation and Egger's linear regression test. All statistical analyses and an assessment of the risk of bias were performed using Review Manager Version 5.3 (RevMan; The Cochrane Collaboration 2012; The Nordic Cochrane Center, Copenhagen, Denmark) and STATA software, V.14.0 (Stata Corporation, College Station, TX). p value of less than 0.05 was considered statistically significant.

RESULTS

Literature Search

Our systematic search identified 902 articles. After the removal of duplicates, 710 articles were screened. After screening the titles and abstracts, we reviewed 59 articles in detail. Among the remaining 59 articles, 33 were protocol articles, six were different designs, three were conference proceedings, three examined low-dose vitamin C, two examined enteral vitamin C, and one did not provide mortality or any secondary outcomes; all of these were subsequently excluded. Two studies did not provide the number of patients who survived or died, and we were unable to calculate these numbers from provided mortality rates (⁴ ^, ¹⁹).

A total of 11 RCTs (^20–29) enrolling 1,737 patients were included in the final meta-analysis. The PRISMA flowchart of the study selection is shown in Figure 1, and the study characteristics are summarized in Table S2 (https://links.lww.com/CCM/G747). The sample size ranged from 28 to 501. Five were single-center RCTs (²² ^, ²³ ^, ²⁵ ^, ²⁸ ^, ²⁹), five were multicenter RCTs (⁹ ^, ²⁰ ^, ²⁴ ^, ²⁶ ^, ²⁷), and one was a two-center RCT (²¹). Sepsis was diagnosed based on the Sepsis-2 definition in two studies (²⁴ ^, ²⁵) and the Sepsis-3 definition in seven studies (^20–23 ^, ²⁶ ^, ²⁸ ^, ²⁹). In the other two studies, patients with suspected or confirmed infection who required vasopressors were included (⁹ ^, ²⁷). Six trials were double blind (⁹ ^, ²¹ ^, ^24–27), one trial was single blind (²³), and the other three trials were open label where only standard treatment for sepsis without placebo was performed in the control groups (²⁰ ^, ²² ^, ²⁸). One study did not mention whether it was double blind, single blind, or open label (²⁹). The characteristics of the included patients, sources of infection, and inclusion and exclusion criteria of each study are summarized in Table 1, Table S3 (https://links.lww.com/CCM/G748), and Table S4 (https://links.lww.com/CCM/G749), respectively. The reported mean/median age of participants ranged from 54 to 70 years in the vitamin C group and 56 to 69 years in the control group. Furthermore, 47.1–71.4% of participants in the vitamin C group and 39.1–78.6% of participants in the control group were males. The SOFA score ranged from 8.0 to 11.8 and 7.9 to 12.4 in the vitamin C and control groups, respectively. The median control SOFA score was 9.2 (IQR, 8.4–10.3).

TABLE 1. - The Characteristics of Included Patients

References		Age, Mean (sd)	Male, % (n/N)	Vasopressors, % (n/N)	Mechanical Ventilation, % (n/N)	Sequential Organ Failure Assessment Score
Sevransky et al (⁹)	HAT therapy	62 (51–69)^a	55.2 (139/252)	36.9 (93/252)	43.7 (110/252)	9.4 (3.6)
Sevransky et al (⁹)	Control	61 (50–72)^a	53.8 (134/249)	39.1 (97/249)	38.6 (96/249)	8.9 (3.5)
Lv et al (²⁹)	Vitamin C	58.7 (14.3)	49.2 (30/61)	58.9 (33/56)	50.0 (28/56)	8.6 (2.9)
Lv et al (²⁹)	Control	60.2 (14.1)	51.8 (29/56)	57.4 (35/61)	50.8 (31/61)	8.9 (3.1)
Mohamed et al (²⁸)	HAT therapy	58.7 (14.9)	68.9 (31/45)	100 (45/45)	48.8 (22/45)	11.2 (3.0)
Mohamed et al (²⁸)	Control	59.4 (15.0)	74.4 (32/43)	100 (43/43)	46.5 (20/43)	10.9 (3.8)
Moskowitz et al (²⁷)	HAT therapy	68.9 (15.0)	56.4 (57/101)	100 (101/101)	47.5 (48/101)	9.1 (3.5)
Moskowitz et al (²⁷)	Control	67.7 (13.9)	54.6 (54/99)	100 (99/99)	44.4 (44/99)	9.2 (3.2)
Hwang et al (²⁶)	Vitamin C and thiamine	70 (62–76)^a	37.7 (20/53)	100 (53/53)	22.6 (12/53)^d	8.0 (6.0–10.0)^a
Hwang et al (²⁶)	Control	69 (62–74)^a	37.9 (22/58)	100 (58/58)	24.1 (14/58)^d	8.0 (6.0–10.0)^a
Chang et al (²³)	HAT therapy	59.5 (15.0)	57.5 (22/40)	55.0 (22/40)	75.0 (30/40)	9.6 (4.0)
Chang et al (²³)	Control	63.7 (12.8)	52.5 (21/40)	60.0 (24/40)	80.0 (32/40)	10.1 (7.6)
Iglesias et al (²¹)	HAT therapy	70.0 (12.0)	47.1 (32/68)	82.4 (56/68)	50.0 (34/68)	8.3 (3.0)
Iglesias et al (²¹)	Control	67.0 (14.0)	39.1 (27/69)	68.1 (47/69)	50.7 (35/69)	7.9 (3.5)
Wani et al (²²)	HAT therapy	59 (25–72)^a	56.0 (28/50)	76.0 (38/50)^c	6.0 (3/50)	9.2 (3.5)
Wani et al (²²)	Control	56 (25–72)^a	62.0 (31/50)	92.0 (46/50)^c	6.0 (3/50)	9.4 (3.7)
Fujii et al (²⁰)	HAT therapy	61.9 (15.9)	63.6 (68/107)	92.5 (99/107)	61.7 (66/107)	8.6 (2.7)
Fujii et al (²⁰)	Control	61.6 (13.9)	62.5 (65/104)	93.3 (97/104)	62.5 (65/104)	8.4 (2.7)
Fowler et al (²⁴)	Vitamin C	54 (39–67)^a	53.6 (45/84)	64.3 (54/84)	100.0 (84/84)	9.8 (3.2)^b
Fowler et al (²⁴)	Control	57 (44–70)^a	54.2 (45/83)	71.1 (59/83)	100.0 (83/83)	10.3 (3.1)^b
Zabet et al (²⁵)	Vitamin C	64.1 (16.0)	71.4 (10/14)	100 (14/14)	Not reported	11.8 (2.2)
Zabet et al (²⁵)	Control	63.7 (13.8)	78.6 (11/14)	100 14/14)	Not reported	12.4 (3.0)

HAT therapy = hydrocortisone, vitamin C (ascorbic acid), and thiamine.

^aThe value was reported as median (interquartile range).

^bThe Sequential Organ Failure Assessment (SOFA) score was modified, eliminating a bilirubin component from SOFA score.

^cThe percentage and number of septic shock.

^dMechanical ventilation at the enrollment.

Figure 1.:
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart. Identification and selection of studies for inclusion. RCT = randomized controlled trial.

Risk of Bias Assessment

We examined the risk of bias of the included 11 RCTs, and the full details are shown in the risk of bias summary (Fig. S1, https://links.lww.com/CCM/G750) and on the risk of bias graph (Fig. S2, https://links.lww.com/CCM/G751). All 11 studies were considered as "low risk" for random sequence generation (selection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Eight studies were considered as "low risk" for allocation concealment (selection bias) (⁹ ^, ^20–24 ^, ²⁶ ^, ²⁷), and allocation concealment could not be assessed in three studies due to lack of information (²⁵ ^, ²⁸ ^, ²⁹). Furthermore, five studies were considered as "low risk" (⁹ ^, ²¹ ^, ^24–26), and five were considered as "high risk" for blinding of participants and personnel (performance bias) (²⁰ ^, ²² ^, ²³ ^, ²⁷ ^, ²⁸). One study was considered as "high risk" (²⁰), and five were considered as "low risk" for blinding of outcome assessment (²¹ ^, ²³ ^, ²⁴ ^, ²⁶ ^, ²⁷). We were unable to assess the blinding of outcome assessment in the five other studies due to a lack of information (⁹ ^, ²² ^, ²⁵ ^, ²⁸ ^, ²⁹). Five studies were considered as "low risk" (⁹ ^, ²⁰ ^, ²⁴ ^, ²⁶ ^, ²⁷), and the remaining six were considered as "high risk" for other biases (^21–23 ^, ²⁵ ^, ²⁸ ^, ²⁹).

Primary Outcomes

All 11 RCTs enrolling 1,737 patients reported short-term mortalities, as shown in Figure 2. High-dose IV vitamin C was not associated with a statistically significant reduction in short-term mortality (RR, 0.88; 95% CI, 0.73–1.06; p = 0.17). Unimportant heterogeneity was observed (I ² = 29%).

Secondary Outcomes

Nine studies reported the duration of vasopressor use (⁹ ^, ^20–23 ^, ²⁵ ^, ²⁶ ^, ²⁸ ^, ²⁹), and the use of IV high-dose vitamin C was associated with significantly shorter duration of vasopressor use (SMD, –0.35; 95% CI, –0.63 to –0.07; p < 0.01; I ² = 80%). Eight studies reported a decrease in the SOFA score at 72–96 hours (⁹ ^, ²⁰ ^, ²¹ ^, ²³ ^, ²⁴ ^, ²⁶ ^, ²⁸ ^, ²⁹), and the use of IV high-dose vitamin C was associated with a significantly greater decrease in the SOFA score at 72–96 hours (SMD, –0.20; 95% CI, –0.32 to –0.08; p < 0.01; I ² = 16%). Four studies reported ventilator-free days (²⁰ ^, ²¹ ^, ²⁴ ^, ²⁶), with no significant difference between the vitamin C and control groups (SMD, 0.00; 95% CI, –0.16 to 0.15; p = 0.95; I ² = 0%). Eight studies reported ICU LOS (⁹ ^, ²⁰ ^, ²¹ ^, ²³ ^, ²⁵ ^, ²⁶ ^, ²⁸ ^, ²⁹), with no significant difference between the vitamin C and control groups (SMD, 0.05; 95% CI, –0.06 to 0.16: p = 0.36; I ² = 0%). Six studies reported hospital LOS (⁹ ^, ^20–22 ^, ²⁶ ^, ²⁸) with no significant difference between the vitamin C and control groups (SMD, 0.03; 95% CI, –0.09 to 0.14; p = 0.65; I ² = 2%). Forest plots of these variables are shown in Figure S3 (https://links.lww.com/CCM/G752). Substantial heterogeneity was only observed in the duration of vasopressor use (I ² = 75%), and unimportant heterogeneity was observed for all other secondary outcomes as described in Figure S3 (https://links.lww.com/CCM/G752).

Subgroup analyses based on the severity of sepsis (SOFA score ≥ the median of included studies vs < the median of included studies) and the type of intervention (HAT therapy vs non-HAT therapy) were also performed; the results are shown in Figure 3. IV high-dose vitamin C was not associated with lower short-term mortality regardless of the median control SOFA scores of included studies (SOFA score ≥ 9.2: RR, 0.85; 95% CI, 0.62–1.15; p = 0.29; I ² = 49% and SOFA score < 9.2: RR, 0.90; 95% CI, 0.71–1.14; p = 0.37; I ² = 8%). Seven studies included in this meta-analysis investigated HAT therapy (⁹ ^, ^20–23 ^, ²⁷ ^, ²⁸), and four studies investigated non-HAT therapy (^24–26 ^, ²⁹); subgroup analysis of these two groups independently also did not demonstrate lower short-term mortality (HAT therapy: RR, 1.00; 95% CI, 0.84–1.19; p = 0.00; I ² = 0% and non-HAT therapy: RR, 0.65; 95% CI, 0.41–1.03; p = 0.62; I ² = 48%). In this analysis, the study by Hwang et al (²⁶) was included in non-HAT therapy since not all patients received hydrocortisone.

Figure 3.:
Forest plot of high-dose vitamin C versus control: short-term mortality based on the severity of sepsis (Sequential Organ Failure Assessment [SOFA] score ≥ 9.2 vs < 9.2) and the type of intervention (hydrocortisone, vitamin C [ascorbic acid], and thiamine [HAT therapy] vs non-HAT therapy). df = degrees of freedom, M-H = Mantel-Haenszel.

HAT therapy was significantly associated with hypernatremia in one study (²³), and other adverse events for each study were shown in Table S5 (https://links.lww.com/CCM/G753).

Sensitivity Analysis

Sensitivity analyses of the subgroups based on the study designs (double-blind vs nondouble-blind RCT and single-center vs multicenter RCT) showed that the use of IV high-dose IV vitamin C was not associated with lower short-term mortality (double-blind RCTs: RR, 0.87; 95% CI, 0.64–1.18 and non-double-blind RCTs: RR, 0.90; 95% CI, 0.70–1.15 and single-center RCTs: RR, 0.75; 95% CI, 0.51–1.10 and multicenter RCTs: RR, 0.94; 95% CI, 0.76–1.16, respectively) (Fig. S4, https://links.lww.com/CCM/G754). Sensitivity analysis based on the dose of vitamin C also showed that the use of both higher dose and lower dose vitamin C was not associated with lower short-term mortality (higher dose: RR, 0.67; 95% CI, 0.31–1.41 and nondouble-blind RCTs: RR, 0.95; 95% CI, 0.80–1.12, respectively) (Fig. S4, https://links.lww.com/CCM/G754).

Publication Bias

We did not detect any evidence of publication bias when we visually assessed funnel plots (Fig. S5, https://links.lww.com/CCM/G755). We also statistically assessed publication bias using Begg's test for rank correlation (p = 0.276) and Egger's linear regression test (p = 0.258).

DISCUSSION

This study is a systematic review and meta-analysis of the effect of IV high-dose vitamin C on mortality of patients with sepsis. Eleven RCTs (n = 1,737 patients) were included in the final analysis. The use of IV high-dose vitamin C in patients with sepsis was not associated with lower short-term mortality regardless of the combination with thiamine and hydrocortisone but was associated with significantly shorter duration of vasopressor use and greater decline in the SOFA score at 72–96 hours.

Vitamin C is known to be a cofactor for biosynthetic enzymes that enhance vasopressor synthesis, such as norepinephrine and vasopressin (³), and preclinical research also suggests that vitamin C restores vascular responsiveness to vasopressors and limits endothelial dysfunction (³⁰). These mechanisms may explain the shortened duration of vasopressor use and a greater decline in the SOFA score with vitamin C therapy. A previous study reported that a greater decline in SOFA scores at 72 hours in patients with sepsis was associated with lower in-hospital mortality (³¹). In addition, a previous systematic review and meta-regression analysis reported that treatment targeting a reduction in the SOFA score, as opposed to a fixed SOFA score goal, was more reliably associated with a reduction in mortality (³²). In this meta-analysis, the use of IV high-dose vitamin C was not associated with lower short-term mortality, although it was significantly associated with a greater decline in SOFA score at 72–96 hours. The interpretation of these results requires caution as we should not overly rely on surrogate outcomes instead of patient-centered outcomes such as mortality (³³).

Subgroup analysis regarding HAT therapy was not associated with lower short-term mortality in patients with sepsis, which suggests that the addition of hydrocortisone and thiamine to vitamin C therapy does not improve short-term mortality in these patients.

Adverse effects of high-dose vitamin C were rare. One study investigating HAT therapy reported a significantly increased prevalence of hypernatremia that the authors attributed to the adverse effects of hydrocortisone (²³). In other studies, it was unclear whether reported adverse events were associated with the use of IV high-dose vitamin C. A recent systematic review described inconsistent evidence regarding the adverse effects or events associated with high-dose vitamin C (³⁴); however, there are reports of oxalate nephropathy, hypernatremia, glucometer error, and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Although clinicians should monitor for the above potential adverse effects, high-dose vitamin C therapy is deemed relatively safe.

There are several limitations to this study. First, it was challenging to assess the timing of vitamin C initiation due to inconsistent documentation and data availability in most studies. It was previously suggested that vitamin C administered as early as possible after the onset of sepsis was most effective (³⁰), but in most included studies, a delay in the administration was allowed secondary to the process of randomization and assignment of treatment. Second, it was difficult to assess the effect of hydrocortisone because it was used in most studies as a part of routine standard therapies. The association between IV high-dose vitamin C with significantly shorter duration of vasopressors and greater decline in SOFA score at 72–96 hours is consistent with the previously reported effect of hydrocortisone therapy (³⁵ ^, ³⁶). In addition, the duration of vasopressors had a substantial heterogeneity among studies, and the result of this subgroup analysis should be interpreted with caution. Third, varying doses of vitamin C were used in the studies included in this meta-analysis. Most of the studies used HAT therapy, which administered 1.5 g of vitamin C every 6 hours, whereas some studies administered 25 mg/kg every 6 hours or more. We believe that the difference in doses of vitamin C was less likely to affect the result of this study as our sensitivity analysis revealed that both higher and lower doses were not associated with lower short-term mortality.

In this systematic review and meta-analysis, treatment with IV high-dose vitamin C therapy was not shown to improve short-term mortality of patients with sepsis regardless of the combination with thiamine and hydrocortisone, whereas it was associated with significantly shorter duration of vasopressor use and greater decline in the SOFA score at 72–96 hours.

ACKNOWLEDGMENTS

We would like to thank Dr. Zhanguo Liu, Dr. Tomoko Fujii, Dr. Rinaldo Bellomo, Dr. Tae Gun Shin, Dr. Won Young Kim, and Dr. Jonathan Sevransky for providing information that was relevant to our study.

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Keywords:

hydrocortisone; vitamin C (ascorbic acid), and thiamine therapy; sepsis; septic shock; thiamine; vitamin C

Supplemental Digital Content

Iv Vitamin C For Sepsis

Source: https://journals.lww.com/ccmjournal/abstract/9000/effect_of_iv_high_dose_vitamin_c_on_mortality_in.95105.aspx

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Iv Vitamin C For Sepsis