The DOI matches its Crossref record; 30 of the 32 references it cites were found in a registry or an index; 7 of the 17 sources its claims cite were checked for support.
Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure
Open accessAbstract
Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.
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Claims the paper makes
21 Own result · 17 Own method · 6 Sources not found · 3 Supported · 3 Partly supported · 3 No full text of the sources · 2 Own interpretation · 1 Couldn’t confirm · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“First, CITRIS-ALI as proposed was based on a previously performed phase 1 safety trial of vitamin C administered to patients in the very early stages of severe sepsis, not ARDS.15”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
What the sources say
- Partly supportedcites [15] 15. Fowler AA III, Syed AA, Knowlson S, et al; Medical Respiratory Intensive Care Unit Nursing. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12: 32. doi:10.1186/1479-5876-12-32 sourceExperimental — accuracy not yet measured
The Methods (Patient enrollment) describe a phase I intravenous ascorbic acid trial in patients meeting severe-sepsis criteria within 48 hours of ICU admission, supporting the description of an early severe-sepsis trial. But the Results (Enrolled study patients) state that 19 patients had ARDS at entry, contradicting the claim’s “not ARDS” qualification. This paper does not establish what CITRIS-ALI was based on. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Delayed quantification of these biomarkers in CITRIS-ALI compared with early vitamin C infusion in severe sepsis may explain results discordant with those of previous studies of vitamin C in severe sepsis.15”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Supportedcites [15] 15. Fowler AA III, Syed AA, Knowlson S, et al; Medical Respiratory Intensive Care Unit Nursing. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12: 32. doi:10.1186/1479-5876-12-32 sourceExperimental — accuracy not yet measured
The Methods (Patient enrollment; page unavailable) report that intravenous ascorbic acid began 2–4 hours after randomization in patients with severe sepsis. The Results (Impact of ascorbic acid infusion on biomarkers; page unavailable) report early reductions in CRP and procalcitonin. The comparison with CITRIS-ALI and the proposed explanation for discordant results are the citing authors’ inference, not a finding attributed to this 2014 trial. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: C-reactive protein and thrombomodulin are valid biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, vitamin C prevented neutrophil extracellular trap formation, a biological event in activated neutrophils that promotes vascular injury.25”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Partly supportedcites [25] 25. Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients. 2013;5(8): 3131-3151. doi:10.3390/nu5083131 sourceExperimental — accuracy not yet measured
The Results (section 3.7) show that vitamin C significantly reduced NET formation in activated human neutrophils, rather than preventing it entirely. The Discussion (section 4) describes potential damage to lung endothelial cells from NET formation in septic mice, but does not establish vascular injury as an observed outcome. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Trans- fer out of the ICU by hour 168 or less occurred in 25% of pa- tients in the vitamin C group (21/84) vs 12.5% in the placebo group (10/83) (χ 2 = 4.63; P = .03; difference, 12.95% [95% CI, 1.16% to 24.73%; P = .31]).”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours”
- Also stated in: § Primary Outcomes · plain
“There was no statistically significant difference in mSOFA scores between placebo and the vitamin C-infused patients from enrollment to 96 hours”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The modified Sequential Organ Failure Assessment score is a valid measure of organ failure in patients with sepsis and ARDS.
- Also stated in: § Primary Outcomes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No unexpected study-related adverse events occurred during the trial.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Adverse Events
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33)”
- Also stated in: § Primary Outcomes · plain
“There were no significant differences between the vitamin C group and placebo group in the C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94; 95% CI, -8.23 to 24.1; P = .33)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: C-reactive protein and thrombomodulin are valid biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.
- Also stated in: § Primary Outcomes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Forty-three of the 46 prespecified secondary outcomes were not significantly different between the vitamin C group and the placebo group”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Kaplan-Meier survival curves for the 2 groups were significantly different by the Wilcoxon test (χ 2 1 = 6.5;P = .01).”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70)at 168 hours”
- Also stated in: § Primary Outcomes · plain
“or thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69; 95% CI, -2.8 to 4.2; P = .70)assessed at 168 hours”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: C-reactive protein and thrombomodulin are valid biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.
- Also stated in: § Primary Outcomes · plain
- It may state two separate claims as one. 24
- Probably not a substantial claim. 21
- The quote only partly states this claim. 2
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“In accordance with these calculations, CITRIS-ALI enrolled 170 patients (85 per group) to allow for 10% dropouts, providing a statistical power of 80%, with an α < .05.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Statistical Analysis
What the sources say
- Could not verifycites [15] 15. Fowler AA III, Syed AA, Knowlson S, et al; Medical Respiratory Intensive Care Unit Nursing. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12: 32. doi:10.1186/1479-5876-12-32 sourceExperimental — accuracy not yet measured
The Results (Enrolled study patients; page unavailable) describe this source’s own trial, which enrolled 26 patients in three groups, not CITRIS-ALI. The Methods (Statistical analysis; page unavailable) give no CITRIS-ALI sample-size calculation. Searches for CITRIS-ALI, 170 patients, simulations, and power found no passage addressing the claim. (LLM, conf=0.76)
plainn = 170- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“for instance, the LUNG SAFE study reported 34% to 45% mortality.5”
- Also stated in: § Discussion · plain
“in the LUNG SAFE study, which included more than 3000 patients with ARDS in 50 countries, all-cause mortality remained high, varying from 34% to 46%, depending on ARDS severity.5”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
What the sources say
- Supportedcites [5] 5. Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788- 800. doi:10.1001/jama.2016.0291 source
The Results (p. 1) report hospital mortality of 34.9% for mild, 40.3% for moderate, and 46.1% for severe ARDS. These figures support the claim’s approximate 34%–46% range by severity. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Discussion · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“The selection of the primary outcomes was based on a previously performed phase 1 trial.15”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Key Points
What the sources say
- Supportedcites [15] 15. Fowler AA III, Syed AA, Knowlson S, et al; Medical Respiratory Intensive Care Unit Nursing. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12: 32. doi:10.1186/1479-5876-12-32 source
The Abstract > Background identifies this study as a phase I trial in patients with severe sepsis. The Abstract > Methods names its primary safety and tolerability endpoints and the additional outcomes it monitored, supporting its identification as the earlier trial used to inform outcome selection. Our copy has no page numbers for these passages. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A report from US hospitals revealed declining ARDS mortality, likely because of both improved supportive care and regimented approaches to mechanical ventilation.4”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Partly supportedcites [4] 4. Cochi SE, Kempker JA, Annangi S, Kramer MR, Martin GS. Mortality trends of acute respiratory distress syndrome in the United States from 1999 to 2013. Ann Am Thorac Soc. 2016;13(10):1742-1751. doi:10.1513/AnnalsATS.201512-841OC sourceExperimental — accuracy not yet measured
The Results report a decline in U.S. ARDS-related deaths and age-adjusted mortality rates from 1999 to 2013. But the study used national death certificates, not a report from hospitals, and the Discussion (Dataset) says it cannot determine the reasons for the decline. It does not establish improved supportive care or mechanical-ventilation approaches as causes. (LLM, conf=0.89)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After cessation of vitamin C infusion at 96 hours, vitamin C levels declined but remained significantly elevated at hour 168 (median, 46 μmol/L; IQR, 19-66) compared with placebo”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At day 28, mortality was 46.3% (38/82) in the placebo group vs 29.8% (25/84) in the vitamin C group (χ 2 = 4.84; P = .03;between-group difference, 16.58% [95% CI, 2% to 31.1%])”
- Also stated in: § Discussion · plain
“although vita-min C compared with placebo was associated with a significant reduction in 28-day all-cause mortality”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasma vitamin C levels sampled at trough periods before infusion had increased significantly in vitamin C-infused patients by hours 48 (median, 166 μmol/L; IQR, 88-376) and 96 (median, 169 μmol/L; IQR, 87-412) compared with placebo patients by hours 48 (median, 23 μmol/L; IQR, 9-37) and 96 (median, 26 μmol/L; IQR, 9-41)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of hospital-free days in the vitamin C group vs the placebo group was 22.6 vs 15.5, respectively (mean difference, 6.69; 95% CI, 0.3 to 13.8; P = .04)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Two patients were lost to follow-up.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Primary Outcomes
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasma vitamin C levels in all patients were subnormal at enrollment (<28 μmol/L), with no significant difference between groups (median for vitamin C-infused patients vs placebo, 22 vs 22 μmol/L [interquartile range {IQR}, 8-39 vs 11-37]; P = .49).”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of ventilator-free days was 13.1 in the vitamin C group vs 10.6 in the placebo group (mean difference, 2.47;”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
plainn = 167- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of ICU-free days to day 28 was 10.7 in the vita- min C group vs 7.7 in the placebo group (mean difference, 3.2; 95% CI, 0.3 to 5.9; P = .03)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Vitamin C-infused patients exhibited a significant reduction in 28-day all-cause mortality, although the P value was not adjusted for multiple comparisons.”
- Also stated in: § Conclusions · plain
“All-cause mortality to day 28, % | | | 84 | 29.8 | 38 | 82 | 46.3 | -0.17 | .03”
- Also stated in: § Limitations · plain
“Gehan-Breslow-Wilcoxon test, P = .01HR, 0.55 (95% CI, 0.33-0.90)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Conclusions · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Significance was set at α = .05and a Holm-Bonferroni correction for 3 co-primary end points was conducted.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fourth, the dosage of vitamin C used in this trial (50 mg/kg every 6 hours for 96 hours) may be insufficient for optimal care of sepsisassociated ARDS.Higher vitamin C dosages or longer administration times may have produced different results.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Multiple imputation with a pattern-mixture model with control-based pattern imputation was used, with 50 imputed data sets created and analyzed to examine the effect of monotone missing data.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Blinding was maintained by the investigational pharmacy at each institution.Investigators were blinded from onset of enrollment to completed analysis of primary and secondary outcomes.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Randomization, Masking, and Study Drug Administration
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of a potential for type I error caused by multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Patients were randomized 1:1 to receive vitamin C or placebo (Figure 1), using randomization generated by the VCU Health Investigational Drug Service by means of Research Randomizer at http://www.randomizer.org.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Randomization, Masking, and Study Drug Administration
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For organ system failure, the SOFA score was modified, eliminating bilirubin during the blinded analysis period as a result of many missing values because clinicians determined that bilirubin measurement was not clinically indicated (mSOFA, range from 0 [normal organ function] to 20 [worst organ function]).”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Study Measurements and Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: The modified Sequential Organ Failure Assessment score is a valid measure of organ failure in patients with sepsis and ARDS.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Fifth, given the absence of previous clinical data, this proof-ofconcept trial was designed to measure the effect of ascorbic acid on organ failure and laboratory measures of inflammation in patients with severe sepsis rather than mortality.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CITRIS-ALI enrollment required fully developed ARDS with endotracheal intubation, which could have delayed vitamin C administration in the treatment group and possibly limited the ability to detect an effect on mSOFA scores and biomarkers.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Three patients were excluded after randomization because of a subsequent diagnosis of diffuse alveolar hemorrhage (n = 2) and acute eosinophilic pneumonia (n = 1).None of these patients received vitamin C.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Characteristics of the Patients
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, differences in baseline characteristics of this necessarily heterogeneous population may have influenced mortality.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sixth, death and ICU graduation rates between the 2 groups were dissimilar, thus rendering the results susceptible to internal selection bias.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Vitamin C increased alveolar fluid clearance by preventing activated neutrophil accumulation in alveolar spaces, limiting alveolar epithelial water-channel damage, and promoting their increased expression.14”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Not checked — no full text of the sourcecites [14] 14. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide- induced acute lung injury. Crit Care Med. 2011;39 (6):1454-1460. doi:10.1097/CCM.0b013e3182120cb8 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“A cute respiratory distress syndrome (ARDS) is a common sepsis-associated organ injury and results in significant mortality [1][2][3][4]”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [1][2][3][4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The median observation time was 28 days (interquartile range, 15-28 days) for the vitamin C group and 28 days (interquartile range, 5-28 days) for the placebo group.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury.[13][14][15]”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Abstract
What the sources say
- Not matchedcites [13][14][15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Patients with sepsis and acute respiratory distress syndrome have worse clinical outcomes than those without sepsis and ARDS, with higher 30-and 60-day mortality and with fewer ventilatorand ICU-free days.27”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Not checked — no full text of the sourcecites [27] 27. Sheu CC, Gong MN, Zhai R, et al. Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS. Chest. 2010;138(3):559- 567. doi:10.1378/chest.09-2933
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Patients with sepsis have a high mortality and accounted for $23.7 billion in US hospital costs in 2013.26”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Discussion
What the sources say
- Not matchedcites [26] 26. Torio C, Moore B. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013: Statistical Brief #204. Rockville, MD: Agency for Healthcare Research & Quality; 2006-2016.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The CITRIS-ALI protocol was approved by the institutional review boards at each of 7 participating medical centers.Written informed consent was obtained from patients or patients' legally authorized representatives.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Study Oversight
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The modified Sequential Organ Failure Assessment score is a valid measure of organ failure in patients with sepsis and ARDS.
“For organ system failure, the SOFA score was modified, eliminating bilirubin during the blinded analysis period as a result of many missing values because clinicians determined that bilirubin measurement was not clinically indicated (mSOFA, range from 0 [normal organ function] to 20 [worst organ function]).”
The paper relies on this without support.
C-reactive protein and thrombomodulin are valid biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.
“plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“The recent clinical trial did not find the effect of intravenous vitamin C infusion on organ failure and biological markers of inflammation and vascular injury in patients with sepsis and acute respiratory distress syndrome, but vitamin C compared with the placebo was associated with a significant reduction in 28-day all-cause mortality [199].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [199]
In the citing paper
“One study reported reduced vasopressor use at 168 h [523].”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [523]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
“median at baseline, 22 vs 22 μM [IQR, 8-39 vs 11-37], P = .68”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
“22 vs 22 μmol/L [interquartile range {IQR}, 8-39 vs 11-37]; P = .49”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“25% of pa- tients in the vitamin C group (21/84) vs 12.5% in the placebo group (10/83)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
Reported 12.5 · recomputed 12.048193
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Characteristics of the Patients
“A total of 1262 eligible patients were identified, of whom 1062 were excluded because of the diagnoses listed in Figure 1.”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Statistical Analysis
“1262 Patients screened for eligibility 1092 Excluded”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| Net fluid balance to median (IQR), mL | 0 | 83 | 1604 | 2927 | 79 | 1901 | 3034 | -3759 (-1123 to 373) | .32 |”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Conclusions
Reported -3759 · recomputed -375
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
“(χ 2 = 4.63; P = .03; difference, 12.95% [95% CI, 1.16% to 24.73%; P = .31])”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Secondary Outcomes
“(χ 2 = 4.63; P = .03;”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Key Points
“oxygenation index (FiO 2 × mean airway pressure/PO 2 ) (if ventilated)”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Conclusions
“e FiO 2 × mean airway pressure/PO 2 × 100.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
“Plasma vitamin C levels in all patients were subnormal at enrollment (<28 μmol/L), with no significant difference between groups”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Vitamin C Pharmacokinetic Findings
“median for vitamin C-infused patients vs placebo, 22 vs 22 μmol/L [interquartile range {IQR}, 8-39 vs 11-37]”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| | 168 | 72 | 22.2 | | 59 | 10.2 | | 10 | .07 |”
§ Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure The CITRIS-ALI Randomized Clinical Trial > Conclusions
Reported 10 · recomputed 12
Citations
Cites
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Self-citation
Cited by
Sorted by citations
Items 101–200 of 825
Rosengrave, P., Spencer, E. S., Williman, J. A., Mehrtens, J. E., Morgan, S., Doyle, T., Heyden, K. V. D., Morris, A., Shaw, G. M., & Carr, A. C. (2022) · Critical Care · doi:10.1186/s13054-022-03900-w · Cited by 72
Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice
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COVID-19 Respiratory Failure: Targeting Inflammation on VV-ECMO Support
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Mortality in septic patients treated with vitamin C: a systematic meta-analysis
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“Sepsis represents a life-threatening condition whose pathophysiology is based on dysregulated inflammatory responses which are accompanied by low levels of antioxidants [17, 19, 49].”
BackgroundResultInfluentialIba, T., Maier, C. L., Helms, J., Ferrer, R., Thachil, J. V., & Levy, J. H. (2024) · Annals of Intensive Care · doi:10.1186/s13613-024-01301-6 · Cited by 76
López, V., Vázquez, T., Alonso-Titos, J., Cabello, M., Alonso, A., Beneyto, I., Crespo, M., Díaz‐Corte, C., Franco, A., González-Roncero, F. M., et al. (2020) · Nefrología · doi:10.1016/j.nefro.2020.03.002 · Cited by 66
Majidi, N., Rabbani, F., Gholami, S., Gholamalizadeh, M., Bourbour, F., Rastgoo, S., Hajipour, A., Shadnoosh, M., Akbari, M. E., Bahar, B., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.717816 · Cited by 70
The coronavirus disease (COVID-19) – A supportive approach with selected micronutrients
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Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial
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Thiamine (vitamin B1) in septic shock: a targeted therapy
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“While many focus on the potential benefits of the ascorbic acid component of this drug cocktail [and results from a recent randomized trial is promising in that regard (38)], there has been less focus on the thiamine component (39).”
BackgroundDisease Mechanisms of Perioperative Organ Injury
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The Role of Circulating Cell-Free Hemoglobin in Sepsis-Associated Acute Kidney Injury
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Fiorino, S., Gallo, C. G., Zippi, M., Sabbatani, S., Manfredi, R., Moretti, R., Fogacci, E., Maggioli, C., Loffredo, F. T., Giampieri, E., et al. (2020) · Aging Clinical and Experimental Research · doi:10.1007/s40520-020-01669-y · Cited by 61
Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy*
Wacker, D. A., Burton, S. L., Berger, J. P., Hegg, A. J., Heisdorffer, J., Wang, Q., Medcraft, E. J., & Reilkoff, R. A. (2022) · Critical Care Medicine · doi:10.1097/ccm.0000000000005427 · Cited by 63
“In light of recent findings of the Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI) trial (13), we wished to further investigate the effects of vitamin C on subjects with respiratory failure.”
BackgroundResultInfluentialHistory of scurvy and use of vitamin C in critical illness: A narrative review
Dresen, E., Lee, Z., Hill, A., Notz, Q., Patel, J. J., & Stoppe, C. (2022) · Nutrition in Clinical Practice · doi:10.1002/ncp.10914 · Cited by 67
Overview of oxidative stress and the role of micronutrients in critical illness
Dresen, E., Pimiento, J. M., Patel, J. J., Heyland, D. K., Rice, T. W., & Stoppe, C. (2022) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2421 · Cited by 71
Du, Y., Chen, Y., Li, F., Mao, Z., Ding, Y., & Wang, W. (2023) · Advanced Science · doi:10.1002/advs.202303053 · Cited by 66
Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives
Zhou, K., Qin, Q., & Lu, J. (2025) · Respiratory Research · doi:10.1186/s12931-025-03137-5 · Cited by 65
Unusual Early Recovery of a Critical COVID-19 Patient After Administration of Intravenous Vitamin C
Khan, H. M. W., Parikh, N. M., Megala, S. M., & Predeteanu, G. (2020) · American Journal of Case Reports · doi:10.12659/ajcr.925521 · Cited by 57
Zhao, B., Ling, Y., Li, J., Peng, Y., HUANG, J. C., Wang, Y., Qu, H., Gao, Y., Li, Y., Hu, B., et al. (2020) · Annals of Palliative Medicine · doi:10.21037/apm-20-1387 · Cited by 57
“The recent CITRIS-ALI study (10) showed HDIVC (50 mg/kg actual body weight every 6 hours for 96 hours) reduced 28 day all-cause mortality (29.”
BackgroundMethodLyu, Q., Zheng, R., Chen, Q., Yu, J., Shao, J., & Gu, X. (2022) · Critical Care · doi:10.1186/s13054-022-04175-x · Cited by 63
López, V., Vázquez, T., Alonso-Titos, J., Cabello, M., Alonso, A., Beneyto, I., Crespo, M., Díaz‐Corte, C., Franco, A., González-Roncero, F. M., et al. (2020) · Nefrología (English Edition) · doi:10.1016/j.nefroe.2020.03.017 · Cited by 56
“20 However, there is no further evidence supporting this effect.”
BackgroundCheca, J., & Aran, J. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239317 · Cited by 55
Mahmoodpoor, A., Shadvar, K., Sanaie, S., Hadipoor, M. R., Pourmoghaddam, M. A., & Saghaleini, S. H. (2021) · BMC Infectious Diseases · doi:10.1186/s12879-021-06288-0 · Cited by 57
Liu, C., Sui, H., Li, Z., Sun, Z., Li, C., Chen, G., Ma, Z., Cao, H., & Xi, H. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03382-x · Cited by 58
Enhancing innate immunity against virus in times of COVID-19: Trying to untangle facts from fictions
Larenas‐Linnemann, D. E., Rodríguez‐Pérez, N., Arias‐Cruz, A., Blandón-Vijil, M. V., Del-Rio-Navarro, B. E., Estrada-Cardona, A., Gereda, J. E., Luna-Pech, J. A., Navarrete-Rodriguez, E. M., Onuma‐Takane, E., et al. (2020) · World Allergy Organization Journal · doi:10.1016/j.waojou.2020.100476 · Cited by 62
“…> 0.2g Hemila 2013(60) Disease duration Vitamin C M D R O A=160 P=160 Decrease morbidity in patients with sepsis-related ARDS Mega-dosing: 15g/d IV Fowler 2019 Carr 2020 (154, 155) Zinc M D R O A= 818 P= 902 Pneumonia Children 5 years old The range of zinc doses (0.7 to 1.8 mg zinc/kg), no…”
InfluentialIV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis
Patel, J. J., Ortiz‐Reyes, L., Dhaliwal, R., Clarke, J. G., Hill, A., Stoppe, C., Lee, Z., & Heyland, D. K. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005320 · Cited by 56
“The six studies included in their metaanalysis were included in ours; however, we included an additional five studies (Zabet et al [7], Fowler et al [3], Fowler et al [8], Mohamed et al [26], and Sevransky et al [17]), three of which were IVVC with IV thiamine and IV hydrocortisone in sepsis.”
ResultMatrine Alleviates Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis and Apoptosis
Xiao, Y., Yu, Y., Hu, L., et al. (2023) · Inflammation · doi:10.1007/s10753-023-01833-2 · Cited by 55
COVID-19 in Children: An Ample Review
Ciucă, I. M. (2020) · Risk Management and Healthcare Policy · doi:10.2147/rmhp.s257180 · Cited by 52
Sulaiman, K. A. A., Aljuhani, O. A., Saleh, K. B., Badreldin, H. A., Harthi, A. A., Alenazi, M., Alharbi, A. A., Algarni, R., Harbi, S. A. A., Alhammad, A., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-96703-y · Cited by 54
Acute Respiratory Distress Syndrome and COVID-19: A Literature Review
Hussain, M., Syed, S. K., Fatima, M., Shaukat, S., Saadullah, M., Alqahtani, A., Alqahtani, T., Emran, T. B., Alamri, A. H., Barkat, M. Q., et al. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s334043 · Cited by 59
The LOVIT-COVID Investigators, O. B. O. T. C. C. C. T. G., Florescu, S., Stanciu, D., Zaharia, M., Kosa, A., Codreanu, D., Fareed, K., Kidwai, A., Kaye, C., Coutts, A., et al. (2023) · JAMA · doi:10.1001/jama.2023.21407 · Cited by 55
Preventing the development of severe COVID-19 by modifying immunothrombosis
Morris, G., Bortolasci, C. C., Puri, B. K., OLIVE, L. S., Marx, W., O'Neil, A. E., Athan, E., Carvalho, A. F., Maes, M. H. J., Walder, K. R., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118617 · Cited by 51
ADAM8 signaling drives neutrophil migration and ARDS severity
Conrad, C., Yildiz, D., Cleary, S. J., Margraf, A., Cook, L., Schlomann, U., Panaretou, B., Bowser, J. L., Karmouty‐Quintana, H., Li, J., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.149870 · Cited by 55
Vitamin C in Health and Disease: A Companion Animal Focus
Gordon, D. S., Rudinsky, A. J., Guillaumin, J., Parker, V. J., & Creighton, K. J. (2020) · Topics in companion animal medicine · doi:10.1016/j.tcam.2020.100432 · Cited by 58
Barnes, T. J., Hockstein, M. A., & Jabaley, C. S. (2020) · SAGE Open Medicine · doi:10.1177/2050312120935466 · Cited by 54
Immunotherapy strategies and prospects for acute lung injury: Focus on immune cells and cytokines
Zhu, W., Zhang, Y., & Wang, Y.-H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1103309 · Cited by 55
“, 2009), vitamin C (Fowler et al., 2019; Holford et al., 2020), and vitamin E (Wang Y.”
BackgroundManagement of Sepsis and Septic Shock: What Have We Learned in the Last Two Decades?
Kamath, S., Altaq, H. H., & Abdo, T. (2023) · Microorganisms · doi:10.3390/microorganisms11092231 · Cited by 61
“CITRIS-ALI showed lower mortality with vitamin C in patients with sepsis and ARDS, but this finding was only a secondary exploratory outcome [193].”
Hydrocortisone–Ascorbic Acid–Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock
Wald, E., Sanchez-Pinto, L. N., Smith, C. M., Moran, T., Badke, C. M., Barhight, M. F., & Malakooti, M. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201908-1543le · Cited by 51
“Both high-dose IV ascorbic acid and HAT therapy have been associated with earlier recovery from organ failure, earlier reversal of shock, and lower mortality in adults with sepsis and septic shock (2, 6, 7).”
BackgroundSato, R., Hasegawa, D., Prasitlumkum, N., Ueoka, M., Nishida, K., Takahashi, K., Nasu, M., & Dugar, S. P. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005263 · Cited by 50
“A total of 11 RCTs (20–29) enrolling 1,737 patients were included in the final meta-analysis.”
BackgroundMethodInfluentialLv, Y., Chen, D., Tian, X., Xiao, J., Xu, C., Du, L., Li, J., Zhou, S., Chen, Y., Zhuang, R., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04111-9 · Cited by 52
“As the disease is related to high morbidity and mortality rates, it constitutes a primary public health burden [27, 28].”
BackgroundPersonalized pharmacological therapy for ARDS: a light at the end of the tunnel
Silva, P. L., Pelosi, P. P., & Rocco, P. R. M. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1699531 · Cited by 50
“The CITRIS-ALI trial [100] evaluated whether infusion of vitamin C could attenuate SOFA score and biomarkers related to inflammation (C-reactive protein, procalcitonin), vascular injury (thrombomodulin, angiopoietin-2), and alveolar epithelial injury (receptor for advanced glycation end-products) while inducing the on…”
BackgroundMethodCobre, A. D. F., Surek, M., Vilhena, R. D. O., Böger, B., Fachi, M. M., Momade, D. R. O., Tonin, F. S., Sarti, F. M., & Pontarolo, R. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.03.018 · Cited by 51
Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction
Zheng, H., Xu, Y., Liehn, E. A., & Rusu, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063114 · Cited by 63
“Similarly, other studies have failed to demonstrate the beneficial effects of vitamin C intake on cardiovascular health and other complications [36], including MI [37,38].”
ResultThe prophylaxis and treatment potential of supplements for COVID-19
Sahebnasagh, A., Saghafi, F., Avan, R., Khoshi, A., Khataminia, M., Safdari, M., Habtemariam, S., Ghaleno, H. R., & Nabavi, S. M. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173530 · Cited by 48
A myriad of roles of dendritic cells in atherosclerosis
Zhao, Y., Zhang, J., Zhang, W., & Xu, Y. (2021) · Clinical & Experimental Immunology · doi:10.1111/cei.13634 · Cited by 49
Adjunctive Nutraceutical Therapies for COVID-19
Subedi, L., Tchen, S., Gaire, B. P., Hu, B. R., & Hu, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041963 · Cited by 48
Cui, Y., Qu, F., Zhong, W., Yang, H., Zeng, J., Huang, J., Liu, J., Zhang, M., Zhou, Y., & Guan, C. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154074 · Cited by 53
Role of vitamin C in preventing of COVID-19 infection, progression and severity
Shahbaz, U., Fatima, N., Basharat, S., Bibi, A., Yu, X., Hussain, M. I., & Nasrullah, M. (2022) · AIMS Microbiology · doi:10.3934/microbiol.2022010 · Cited by 51
“When the alveoli in our lungs fill up with fluid, we have acute respiratory distress syndrome (ARDS), which is life-threatening.”
BackgroundInfluentialAre Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?
Catalano, A. A., Iacopetta, D., Ceramella, J., Maio, A. C. D., Basile, G., Giuzio, F., Bonomo, M. G., Aquaro, S., Walsh, T. J., Sinicropi, M. S., et al. (2022) · Foods · doi:10.3390/foods11182884 · Cited by 48
“The recently reported randomized trial in sepsis demonstrated poorer outcomes in those patients receiving vitamin C [88].”
BackgroundSherren, P. B., Ostermann, M., Agarwal, S., Meadows, C. I. S., Ioannou, N., & Camporota, L. (2020) · British Journal of Anaesthesia · doi:10.1016/j.bja.2020.08.050 · Cited by 45
Vankrunkelsven, W., Gunst, J., Amrein, K., Bear, D. E., Berger, M. M., Christopher, K. B., Fuhrmann, V., Hiesmayr, M., Ichaï, C., Jakob, S. M., et al. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.06.005 · Cited by 46
A dissection of SARS‑CoV2 with clinical implications (Review)
Stancioiu, F., Papadakis, G., Kteniadakis, S., Izotov, B. N., Coleman, M. D., Spandidos, D. A., & Tsatsakis, A. M. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4636 · Cited by 46
“In a prospective randomised placebo-controlled double blind trial ‐ CITRIS‐ALI ‐ ascorbate 50 mg/kg or placebo was given q 6 h intravenously for 96 h to 167 patients with sepsis and ARDS; no significant difference was seen at 96 h in organ dysfunction scores (SOFA), inflammation marker CRP or thrombomodulin (for vascu…”
MethodPatterson, T., Isales, C. M., & Fulzele, S. (2021) · Aging and Disease · doi:10.14336/ad.2020.0918 · Cited by 44
“Acute respiratory distress syndrome (ARDS) is one of the severe complications of sepsis [53].”
BackgroundMethodInfluentialMedications in COVID-19 patients: summarizing the current literature from an orthopaedic perspective
Tan, S. H. S., Hong, C. C., Saha, S., Murphy, D. P., & Hui, J. H. P. (2020) · International Orthopaedics · doi:10.1007/s00264-020-04643-5 · Cited by 44
“In a randomized, double-blind, placebo-controlled, multicentre trial, 167 patients with sepsis-induced acute respiratory distress syndrome were randomized to receive either intravenous infusion of high-dose vitamin C or placebo, and while vitamin C did not significantly improve organ dysfunction scores or alter marker…”
BackgroundLykkesfeldt, J., Carr, A. C., & Tveden‐Nyborg, P. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100043 · Cited by 50
The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2024
Shime, N., Nakada, T.-A., Yatabe, T., Yamakawa, K., Aoki, Y., Inoue, S., Iba, T., Ogura, H., Kawai, Y., Kawaguchi, A., et al. (2025) · Journal of Intensive Care · doi:10.1186/s40560-025-00776-0 · Cited by 45
Hemilä, H., & de Man, A. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2020.559811 · Cited by 48
Jung, S., Lee, M., Baek, M. S., & Kim, W. (2022) · Critical Care · doi:10.1186/s13054-021-03872-3 · Cited by 47
“In the CITRIS-ALI trial, the survival curve of the vitamin C group became parallel to that of the placebo group after cessation of treatment [7], suggesting that the favorable effects of vitamin C may decrease over time.”
BackgroundMethodParenteral Vitamin C in Patients with Severe Infection: A Systematic Review
Agarwal, A., Basmaji, J., Fernando, S. M., Ge, F. Z., Xiao, Y., Faisal, H., Honarmand, K., Hylands, M., Lau, V. I., Lewis, K. A., et al. (2022) · NEJM Evidence · doi:10.1056/evidoa2200105 · Cited by 45
COVID-19: Up to 82% critically ill patients had low Vitamin C values
Tomasa-Irriguible, T. M., & Bielsa-Berrocal, L. (2021) · Nutrition Journal · doi:10.1186/s12937-021-00727-z · Cited by 43
Use of Hydrocortisone, Ascorbic Acid, and Thiamine in Adults with Septic Shock
Vail, E. A., Wunsch, H., Pinto, R. L., Bosch, N. A., Walkey, A. J., Lindenauer, P. K., & Gershengorn, H. B. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202005-1829oc · Cited by 41
Micronutrients throughout the Life Cycle: Needs and Functions in Health and Disease
Kumar, M., Kumar, D., Sharma, A., Bhadauria, S., Thakur, A., & Bhatia, A. (2023) · Current Nutrition & Food Science · doi:10.2174/1573401319666230420094603 · Cited by 43
Postbiotics as potential new therapeutic agents for sepsis
Lou, X., Xue, J., Shao, R., Mo, C., Wang, F., & Chen, G. (2023) · Burns & Trauma · doi:10.1093/burnst/tkad022 · Cited by 38
“Highdose intravenous vitamin C in adults with sepsis and acute respiratory distress syndrome reduced 28-day mortality and increased the number of days that patients spent outside of the ICU and hospital [101].”
BackgroundZhao, B., Liu, M., Liu, P., Peng, Y., HUANG, J. C., Li, M., Wang, Y., Xu, L., Sun, S., Qi, X., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.638556 · Cited by 41
“This was partially consistent with the mortality reducing effect of HDIVC on sepsis with acute respiratory distress syndrome reported by Folwer (CITRIS-ALI study) (Fowler et al., 2019) and Hemilä, et al.”
ResultQiao, X., Kashiouris, M. G., L'Heureux, M., Fisher, B. J., Leichtle, S. W., Truwit, J. D., Nanchal, R. S., Hite, R. D., Morris, P. E., Martin, G. S., et al. (2022) · Nutrients · doi:10.3390/nu14204415 · Cited by 44
Self-citationZayed, Y., Alzghoul, B. N., Banifadel, M., Venigandla, H., Hyde, R., Sutchu, S., Khasawneh, M., Borok, Z., Urbine, D., Jantz, M. A., et al. (2021) · Journal of Intensive Care Medicine · doi:10.1177/0885066620987809 · Cited by 38
“While two thirds of patients received corticosteroids in each group this finding was considered exploratory since it did not account for multiple comparisons.(34) Furthermore, a propensity matched retrospective study involving more than 1,100 patients with septic shock found that there was no mortality benefit of trip…”
ResultFujimoto, S., Fujita, Y., Kadota, T., Araya, J., & Kuwano, K. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.619697 · Cited by 40
Ao, G., Li, J., Yang, Y., Wang, Y., Nasr, B., Bao, M., Gao, M., & Qi, X. (2022) · Nutrition in Clinical Practice · doi:10.1002/ncp.10832 · Cited by 39
Roberson, S. W., Nwosu, S., Collar, E. M., Kiehl, A. L., Harrison, F. E., Bastarache, J. A., Wilson, J. E., Mart, M. F., Sevransky, J., Ely, E. W., et al. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.0380 · Cited by 38
Self-citationAtrazine Toxicity: The Possible Role of Natural Products for Effective Treatment
Das, S., Sakr, H. F., Al‐Huseini, I., Jetti, R., Al-Qasmi, S., Sugavasi, R., & Sirasanagandla, S. R. (2023) · Plants · doi:10.3390/plants12122278 · Cited by 37
“Vitamin C supplementation is beneficial against acute respiratory distress syndrome [152] and neurodegenerative diseases such as Alzheimer’s disease [153,154].”
BackgroundSidebotham, D. A., & Barlow, C. J. (2023) · Anaesthesia · doi:10.1111/anae.16161 · Cited by 40
Weiss, S. L., Peters, M. J., Oczkowski, S. J. W., Belley‐Côté, E. P., Buysse, C., Choong, K. L. M., Deep, A., Inwald, D. P., Flori, H. R., Kneyber, M. C. J., et al. (2026) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000003927 · Cited by 46
Simonson, W. (2020) · Geriatric Nursing · doi:10.1016/j.gerinurse.2020.05.002 · Cited by 36
“6 Dr. Hunninghake reports administering intravenous vitamin C to 250,000 patients over his 31 years of practice and describes vitamin C as "The paramount rescue molecule in nature."”
BackgroundSARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment
Khalaf, K., Papp, N., Chou, J. T.-T., Hana, D., Mackiewicz, A. A., & Kaczmarek, M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.570927 · Cited by 39
“placebo in septic patients with ARDS, and they concluded that the vitamin C infusion did not improve either inflammatory markers or organ dysfunction score (176).”
BackgroundCOVID-19 and nutritional deficiency: a review of existing knowledge
Pallath, M. M., Ahirwar, A. K., Tripathi, S. C., Asia, P., Sakarde, A., & Gopal, N. (2021) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2020-0074 · Cited by 38
Patel, J. J., Martindale, R. G., & McClave, S. A. (2020) · Nutrition in Clinical Practice · doi:10.1002/ncp.10566 · Cited by 36
Wald, E., Badke, C. M., Hintz, L. K., Spewak, M. B., & Sanchez-Pinto, L. N. (2021) · Pediatric Research · doi:10.1038/s41390-021-01673-6 · Cited by 35
Micronutrient deficiencies in critical illness
Koekkoek, W. A. C., Hettinga, K. A., de Vries, J. H. M., & van Zanten, A. R. H. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.05.003 · Cited by 39
Liang, B., Su, J., Shao, H., Chen, H., & Xie, B. (2023) · Critical Care · doi:10.1186/s13054-023-04392-y · Cited by 41
“Although several RCTs [27, 28, 34, 35] which delta SOFA score as primary outcome found that IVVC did not significantly improve organ function compared with placebo, our meta-analysis indicated promising results that IVVC could significantly improve delta SOFA score after integrating multiple RCTs, which was validated…”
BackgroundMethodResultInfluentialNutrition in Pediatric Intensive Care: A Narrative Review
Kratochvíl, M., Klučka, J., Klabusayová, E., Musilová, T., Vafek, V., Skříšovská, T., Djakow, J., Havránková, P., Osinová, D., & Štourač, P. (2022) · Children · doi:10.3390/children9071031 · Cited by 41
Dhege, C. T., Kumar, P., & Choonara, Y. E. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124182 · Cited by 37
Moonen, H. P. F. X., & van Zanten, A. R. H. (2020) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000741 · Cited by 35
Cytokine Storm in Novel Coronavirus Disease (COVID-19): Expert Management Considerations
Ansari, A. S. (2020) · Indian Journal of Critical Care Medicine · doi:10.5005/jp-journals-10071-23415 · Cited by 36
Hemilä, H., & Chalker, E. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.590853 · Cited by 34
Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID‐19
May, C. N., Bellomo, R., & Lankadeva, Y. R. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15579 · Cited by 33
“The CITRUS-ALI trial, that used 200 mg/kg/day (16 g/day in an 80 kg patient) of vitamin C for 4 days, however, reduced 28-day mortality from 46% to 30% (Fowler et al., 2019).”
MethodThe Effect of Shionone on Sepsis-Induced Acute Lung Injury by the ECM1/STAT5/NF-κB Pathway
Song, Y., Wu, Q., Jiang, H., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.764247 · Cited by 34
“The activation of neutrophil and macrophage is the pathological hallmark of the immune/inflammatory response in ALI (Fowler et al., 2019; Zhang et al., 2021a).”
BackgroundVitamin supplements in the Era of SARS-Cov2 pandemic
Am, C., Benvenuto, A., Lagattolla, V., Teresa, M., Pasquale, D. L., Giuseppe, C., Giovanni, M., Michele, D. P., Ponziano, E., & Benvenuto, M. (2020) · GSC Biological and Pharmaceutical Sciences · doi:10.30574/gscbps.2020.11.2.0114 · Cited by 39
“There is evidence that Vitamin C infusion may improve sepsis and sepsis-induced multiorgan dysfunction and reduce mortality in patients with sepsis and severe acute respiratory failure [18,21,22]; improvement of lung inflammation, induced by influenza A virus/H1N1, was also reported in patients taking Vitamin C [34].”
BackgroundCan vitamins and/or supplements provide hope against coronavirus?
Michienzi, S. M., & Badowski, M. E. (2020) · Drugs in Context · doi:10.7573/dic.2020-5-7 · Cited by 35
COVID-19 and Fast Foods Consumption: a Review
Bohlouli, J., Moravejolahkami, A. R., Dashti, M. G., Zehi, Z. B., Kermani, M. A. H., Borzoo-Isfahani, M., & Bahreini, N. (2021) · International Journal of Food Properties · doi:10.1080/10942912.2021.1873364 · Cited by 33
“[56] In contrast, the administration of ~15 g/day of IV vitamin C for 4 days decreases mortality in sepsis-related Acute Respiratory Distress Syndrome.”
BackgroundThe role of micronutrient and immunomodulation effect in the vaccine era of COVID-19
Lai, Y.-J., Chang, H.-S., Yang, Y., Lin, T.-W., Lai, W.-Y., Lin, Y., & Chang, C. (2021) · Journal of the Chinese Medical Association · doi:10.1097/jcma.0000000000000587 · Cited by 34
“18 In adaptive immunity, Vit C can enhance the differentiation and proliferation of B and T cells.”
Epigenetic remodeling by vitamin C potentiates plasma cell differentiation
Chen, H.-Y., Almonte-Loya, A., Lay, F.-Y., Hsu, M., Johnson, E. C., González‐Avalos, E., Yin, J., Bruno, R. S., Ma, Q., Ghoneim, H. E., et al. (2022) · eLife · doi:10.7554/elife.73754 · Cited by 37
“The outcomes from these studies were ambiguous as to whether or not the ‘mega dose’ VC was effective in treating these diseases (Nauman et al., 2018; Thomas et al., 2021; Ngo et al., 2019; Magrì et al., 2020; Klimant et al., 2018; Fowler et al., 2019; Marik et al., 2017).”
ResultRole of toll-like receptor-mediated pyroptosis in sepsis-induced cardiomyopathy
Fan, Y., Guan, B., Xu, J., Zhang, H., Liang, Y., & Yang, Z. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115493 · Cited by 35
Honoré, P. M., Spapen, H. D., Marik, P. E., Boer, W., & Straaten, H. M. O. (2020) · Annals of Intensive Care · doi:10.1186/s13613-020-0640-6 · Cited by 31
Dual Role of Hydrogen Peroxide as an Oxidant in Pneumococcal Pneumonia
Mraheil, M. A., Toque, H. A., Pietra, L. L., Hamacher, J., Phanthok, T., Verin, A. D., Gonzales, J., Su, Y., Fulton, D. J., Eaton, D. C., et al. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7964 · Cited by 30
Current Approaches to COVID-19: Therapy and Prevention
Dixit, S., Khatib, K. I., Bandopadhyay, S., Shrivastav, O., & Mhatre, U. (2020) · Indian Journal of Critical Care Medicine · doi:10.5005/jp-journals-10071-23470 · Cited by 30
Krishnamoorthy, V. K., Temkin, N. R., Barber, J. K., Foreman, B. P., Komisarow, J. M., Korley, F. K., Laskowitz, D. T., Mathew, J. P., Hernandez, A. F., Sampson, J. H., et al. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005055 · Cited by 33
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“These include pneumonia, acute respiratory distress syndrome (ARDS), septic shock, coagulation dysfunction, liver dysfunction, and acute kidney failure [7].”
BackgroundInfluentialFan, S., & Ma, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-55257-5 · Cited by 30
Metadata
- Authors
- Fowler, A. A., Truwit, J. D., Hite, R. D., Morris, P. E., DeWilde, C., Priday, A., Fisher, B., Thacker, L. R., Natarajan, R., Brophy, D. F., Sculthorpe, R., Nanchal, R., Syed, A., Sturgill, J., Martin, G. S., Sevransky, J., Kashiouris, M., Hamman, S., Egan, K. F., Hastings, A., Spencer, W., Tench, S., Mehkri, O., Bindas, J., Duggal, A., Graf, J., Zellner, S., Yanny, L., McPolin, C., Hollrith, T., Kramer, D., Ojielo, C., Damm, T., Cassity, E., Wieliczko, A., & Halquist, M.
- Affiliations
- Virginia Commonwealth University (US)
- Froedtert Hospital (US)
- Cleveland Clinic (US)
- University of Kentucky (US)
- Emory University (US)
- Fairview Hospital, Cleveland, Ohio
- Aurora St. Luke's Medical Center (US)
- Corresponding author
- Fowler, Alpha A.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2019-10-01
- Volume
- 322
- Issue
- 13
- Pages
- 1261
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6777268
- OpenAlex
- W2977803759
- Cited by
- 836
- References
- 32
- Citations by year
- 2026: 56 · 2025: 81 · 2024: 68 · 2023: 105 · 2022: 134 · 2021: 181 · 2020: 198 · 2019: 12
- FWCI
- 99.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000058)
- National Heart, Lung, and Blood Institute (UM1HL116885)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50AR072000)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Keywords
- vitamin C, sepsis, acute respiratory distress syndrome, acute respiratory failure, organ failure, Sequential Organ Failure Assessment score, C-reactive protein, thrombomodulin, inflammatory markers, vascular injury, critically ill patients, length of hospital stay
- MeSH terms
- Adult, Aged, Ascorbic Acid, C-Reactive Protein, Double-Blind Method, Female, Humans, Infusions, Intravenous, Intensive Care Units, Male, Middle Aged, Multiple Organ Failure, Respiratory Distress Syndrome, Vitamins, Biomarkers, Thrombomodulin, Sepsis, Organ Dysfunction Scores
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-01, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-01 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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