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Cited by 836Vitamin C and Antioxidants ResearchSepsis Diagnosis and TreatmentRespiratory Support and Mechanisms

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 access
Fowler, Alpha A., Truwit, Jonathon D., Hite, R. Duncan, Morris, Peter E., DeWilde, Christine, Priday, Anna, Fisher, Bernard, Thacker, Leroy R. +28 more·2019·JAMA
DOI 10.1001/jama.2019.11825PMC PMC6777268
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Abstract

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.

Integrity signals

Registry

Crossref · 10.1001/jama.2019.11825

Cites

31 of 32 references verified0 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 17 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    CITRIS-ALI was based on a previously performed phase 1 safety trial of vitamin C in patients in very early stages of severe sepsis, not ARDS.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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 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)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Delayed quantification of biomarkers in CITRIS-ALI compared with early vitamin C infusion in severe sepsis may explain results discordant with previous studies of vitamin C in severe sepsis.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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
      Experimental — accuracy not yet measured
    • Rests on an assumption: C-reactive protein and thrombomodulin are valid biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.
  • Premisecitation

    Vitamin C prevented neutrophil extracellular trap formation, a biological event in activated neutrophils that promotes vascular injury.

    “In addition, vitamin C prevented neutrophil extracellular trap formation, a biological event in activated neutrophils that promotes vascular injury.25”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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 source

      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)

      Experimental — accuracy not yet measured
  • Findingown data

    Transfer out of the ICU by hour 168 or earlier occurred in 25% (21/84) of the vitamin C group and 12.5% (10/83) of the placebo group (χ2=4.63; P=.03; difference, 12.95% [95% CI, 1.16% to 24.73%; P=.31]).

    “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]).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In patients with sepsis and ARDS, intravenous vitamin C compared with placebo did not significantly change the modified Sequential Organ Failure Assessment score from baseline to 96 hours.

    “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”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The modified Sequential Organ Failure Assessment score is a valid measure of organ failure in patients with sepsis and ARDS.
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 2

  • May combine two claims.

    Study design and conductown data

    Sample size was calculated using means, variances, and correlations from another trial; simulations led to enrollment of 170 patients (85 per group) to allow for 10% dropouts, providing 80% power with α < .05.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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 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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The LUNG SAFE study reported high all-cause mortality in ARDS, with values in the 34% to 46% range depending on severity.

    “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”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The primary outcomes were selected based on a previously performed phase 1 trial.

    “The selection of the primary outcomes was based on a previously performed phase 1 trial.15”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A report from US hospitals revealed declining ARDS mortality, likely because of both improved supportive care and regimented approaches to mechanical ventilation.

    “A report from US hospitals revealed declining ARDS mortality, likely because of both improved supportive care and regimented approaches to mechanical ventilation.4”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    After vitamin C infusion was stopped at 96 hours, plasma vitamin C levels declined but remained significantly higher in the vitamin C group at 168 hours (median, 46 μmol/L) than in the placebo group (median, 29 μmol/L).

    “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”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In exploratory analyses without adjustment for multiple comparisons, 28-day all-cause mortality was 46.3% (38/82) in the placebo group and 29.8% (25/84) in the vitamin C group, a between-group difference of 16.58% (95% CI, 2% to 31.1%; P = .03).

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma vitamin C levels before infusion were significantly higher in the vitamin C group than in the placebo group at 48 hours (median, 166 vs 23 μmol/L) and at 96 hours (median, 169 vs 26 μmol/L).

    “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)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Hospital-free days at day 60 were 22.6 in the vitamin C group and 15.5 in the placebo group, with a mean difference of 6.69 (95% CI, 0.3 to 13.8; P = .04).

    “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)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Two patients were lost to follow-up.

    “Two patients were lost to follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At enrollment, plasma vitamin C levels were subnormal (<28 μmol/L) in all patients, with no significant difference between the vitamin C and placebo groups (median, 22 vs 22 μmol/L; P = .49).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Ventilator-free days to day 28 were 13.1 in the vitamin C group and 10.6 in the placebo group, with a mean difference of 2.47 (95% CI, -0.90 to 5.85; P = .15).

    “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;”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Of 167 randomized patients, 103 (62%) completed the study to day 60.

    “Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ICU-free days to day 28 were 10.7 in the vitamin C group and 7.7 in the placebo group, with a mean difference of 3.2 (95% CI, 0.3 to 5.9; P = .03).

    “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)”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In a preliminary study of patients with sepsis and ARDS, vitamin C infusion compared with placebo significantly reduced 28-day all-cause mortality (29.8% vs 46.3%; P=.03; HR 0.55, 95% CI 0.33-0.90, P=.01), but the P value was not adjusted for multiple comparisons.

    “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)”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A Holm-Bonferroni correction for the 3 co-primary endpoints was conducted.

    “Significance was set at α = .05and a Holm-Bonferroni correction for 3 co-primary end points was conducted.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    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 sepsis-associated ARDS, and higher dosages or longer administration times may have produced different results.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Multiple imputation with a pattern-mixture model using control-based pattern imputation was used, with 50 imputed datasets, to examine the effect of monotone missing data.

    “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.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Blinding was maintained by the investigational pharmacy at each institution, and investigators were blinded from enrollment through completed analysis of primary and secondary outcomes.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Secondary endpoints should be interpreted as exploratory because of potential type I error from multiple comparisons.

    “Because of a potential for type I error caused by multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Patients were randomized 1:1 to vitamin C or placebo using randomization generated by the VCU Health Investigational Drug Service with Research Randomizer.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The mSOFA score was modified by eliminating bilirubin during the blinded analysis period because of many missing values.

    “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]).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The modified Sequential Organ Failure Assessment score is a valid measure of organ failure in patients with sepsis and ARDS.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Given the absence of previous clinical data, this proof-of-concept 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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Enrollment required fully developed ARDS with endotracheal intubation, which could have delayed vitamin C administration and possibly limited the ability to detect an effect on mSOFA scores and biomarkers.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States.

    “The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Three patients were excluded after randomization because of subsequent diagnoses of diffuse alveolar hemorrhage (n=2) and acute eosinophilic pneumonia (n=1); none of these patients received vitamin C.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Differences in baseline characteristics of this heterogeneous population may have influenced mortality.

    “Third, differences in baseline characteristics of this necessarily heterogeneous population may have influenced mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Death and ICU graduation rates between the two groups were dissimilar, rendering the results susceptible to internal selection bias.

    “Sixth, death and ICU graduation rates between the 2 groups were dissimilar, thus rendering the results susceptible to internal selection bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ARDS is a common sepsis-associated organ injury and results in significant mortality.

    “A cute respiratory distress syndrome (ARDS) is a common sepsis-associated organ injury and results in significant mortality [1][2][3][4]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1][2][3][4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Median follow-up time was 28 days (IQR 15-28) for vitamin C recipients and 28 days (IQR 5-28) for placebo recipients.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury.

    “Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury.[13][14][15]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13][14][15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Patients with sepsis and ARDS have worse clinical outcomes than those without sepsis and ARDS, with higher 30- and 60-day mortality and fewer ventilator- and ICU-free days.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients with sepsis have high mortality and accounted for $23.7 billion in US hospital costs in 2013.

    “Patients with sepsis have a high mortality and accounted for $23.7 billion in US hospital costs in 2013.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study protocol was approved by the institutional review boards at each of 7 participating medical centers, and written informed consent was obtained from patients or their legally authorized representatives.

    “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.”
    Quote in the paperNot a substantial claim
34 of 34

  • 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.”
2 of 2

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 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.

    “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]

  • One study reported reduced vasopressor use at 168 h with vitamin C.

    “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.

  • Baseline vitamin C comparison has two P values

    Minor

    The figure description gives P = .68 for the baseline comparison, whereas the pharmacokinetic Results give P = .49 for the same medians and interquartile ranges.

  • Placebo ICU-transfer percentage is misstated

    Minor

    Ten of 83 placebo patients is approximately 12.05%, not 12.5%.

    Reported 12.5 · recomputed 12.048193

  • The patient-flow counts disagree with the Results

    Minor

    The Results say 1062 patients were excluded, while the patient-flow figure says 1092 were excluded. The latter count also accounts for the figure's 170 randomized patients out of 1262 screened.

  • Net-fluid-balance estimate falls outside its confidence interval

    Minor

    The reported coefficient, −3759, is outside its stated 95% CI of −1123 to 373. The interval's midpoint is −375, suggesting an error in the coefficient.

    Reported -3759 · recomputed -375

  • Two P values disagree for the ICU-transfer comparison

    Minor

    The same comparison is reported with P = .03 and P = .31. Its stated 95% confidence interval also excludes zero, unlike what P = .31 would suggest for that difference.

  • Oxygenation index has conflicting definitions

    Minor

    The Methods define the index without a factor of 100, but the Table 2 footnote includes that factor. These formulas produce values differing by a factor of 100.

  • Baseline vitamin C values were not subnormal in every patient

    Minor

    The text says all patients had concentrations below 28 μmol/L at enrollment, but the reported upper quartiles were 39 and 37 μmol/L. Thus, at least some patients had values above that threshold.

  • Vasopressor-use difference at 168 hours is incorrect

    Minor

    The table reports 22.2% for vitamin C and 10.2% for placebo, a difference of 12.0 percentage points rather than the listed 10.

    Reported 10 · recomputed 12

8 of 8

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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
DOI
10.1001/jama.2019.11825
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
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 › Epidemiology › 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

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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.

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