Vitamin C and acute respiratory infections H. Hemilä,* R. M.

Douglas†
INT J TUBERC LUNG DIS 3(9):756–761 © 1999 IUATLD
While in the older literature vitamin C has been suggested as hastening convalescence from
pneumonia,3–7,33,35 we are aware of only one controlled trial pertinent to this issue.38 The
subjects in this randomised double-blind placebocontrolled trial were a mixture of hospital patients
in the UK with pneumonia (n 17) and acute exacerbation of chronic bronchitis (n 40), with an
average age of 80 years. Therapeutic vitamin C (0.2 g/day) significantly decreased the score of
respiratory symptoms in patients who were most severely affected when admitted to hospital, and a
decrease bordering on statistical significance was seen in all patients.38 Furthermore, of the six
deaths among the patients during the trial, all due to respiratory infections, five of them were in the
placebo group (n 29), but only one in the vitamin C group (n 28). This is another area where more
work is needed. The possibility that therapeutic supplements could reduce death rates from serious
respiratory infections in marginally nourished and well nourished populations warrants further
careful trials.

Failure of High-Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients with Advanced Cancer
— A Controlled Trial
One hundred and fifty patients with advanced cancer participated in a controlled double-blind study
to evaluate the effects of high-dose vitamin C on symptoms and survival. Patients were divided
randomly into a group that received vitamin C (10 g per day) and one that received a comparably
flavored lactose placebo. Sixty evaluable patients received vitamin C and 63 received a placebo. Both
groups were similar in age, sex, site of primary tumor, performance score, tumor grade and previous
chemotherapy. The two groups showed no appreciable difference in changes in symptoms,
performance status, appetite or weight. The median survival for all patients was about seven weeks,
and the survival curves essentially overlapped. In this selected group of patients, we were unable to
show a therapeutic benefit of high-dose vitamin C treatment. (N Engl J Med 301:687–690, 1979)

High-Dose Vitamin C versus Placebo in the Treatment of Patients with Advanced Cancer Who Have
Had No Prior Chemotherapy — A Randomized Double-Blind Comparison
It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced
cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100
patients with advanced colorectal cancer were randomly assigned to treatment with either high-
dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition,
with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C
therapy showed no advantage over placebo therapy with regard to either the interval between the
beginning of treatment and disease progression or patient survival. Among patients with measurable
disease, none had objective improvement. On the basis of this and our previous randomized study, it
can be concluded that high-dose vitamin C therapy is not effective against advanced malignant
disease regardless of whether the patient has had any prior chemotherapy. (N Engl J Med 1985;
312:137–41.)

Oxalate nephropathy following vitamin C intake within intensive care unit

Clinical Nephrology, Vol. 88 – No. 6/2017 (354-358
Objective: To report a case of acute oxalate nephropathy related to vitamin C intake within the
intensive care unit (ICU). Design: Case report. Setting: ICU and nephrology department of a French
university hospital. Patient: A 57-year-old woman with septic shock related to Legionella
pneumophila pneumonia complicated by acute respiratory distress syndrome and acute kidney
injury who required renal replacement therapy for 75 days. Measurements and main results: A renal
biopsy was performed on day 72 because of persistent anuria and because the patient showed
characteristic features of severe acute oxalate nephropathy. The only cause identified was vitamin C
intake received during hospitalization within the ICU (~ 30 g over 2.5 months). At month 6 after ICU
admission, estimated glomerular filtration rate was 24 mL/min/1.73m2. Conclusion: Compelling
evidence obtained from in-vitro and animal studies suggest that vitamin C, a circulating antioxidant,
may be a valuable adjunctive therapy in critically-ill patients. Data from humans are more conflicting.
Oxalate, a well-known metabolite of vitamin C, is excreted by the kidneys and can exert a toxic effect
on epithelial cells and causes direct tubular damage, and/or it can crystallize within the tubular
lumen. This case highlights an under-recognized secondary adverse event from vitamin C given to
critically-ill patients. The use of high-dose vitamin C should be prescribed with caution in this
population

Antioxidant therapy  in critical care—Is the microcirculation the primary target?

Critical Care Medicine:  September 2007 - Volume 35 - Issue 9 - p S577-S583
This review presents the rationale for the therapeutic use of antioxidants in treating critically ill
patients; it is not a systematic review of the clinical evidence that has been assessed recently by
others. Clinical and nonclinical evidence is presented to support the notion that natural antioxidants
are of therapeutic value in treating cardiovascular shock. Oxidative stress is a major promoter and
mediator of the systemic inflammatory response. The microcirculation is particularly susceptible
to oxidative stress that causes hemodynamic instability, leading to multiple organ failure due
to systemic inflammatory response syndrome. Vitamin C is the antioxidant used experimentally to
demonstrate oxidative stress as a key pathophysiologic factor in septic shock. Pharmacologic studies
reveal that vitamin C (as ascorbate), at supraphysiologic doses, significantly affects the bioavailability
of nitric oxide during acute inflammation, including inhibiting nitric oxide synthetase induction.
Parenteral high-dose vitamin C inhibits endotoxin-induced endothelial dysfunction and
vasohyporeactivity in humans and reverses sepsis-induced suppression of microcirculatory control in
rodents. In severe burn injury, in both animals and patients, parenteral high-dose vitamin C
significantly reduces resuscitation fluid volumes. Therefore, a significant body of pharmacologic
evidence and sound preliminary clinical evidence supports the biological feasibility of using the
exemplary antioxidant, vitamin C, in the treatment of the critically ill.

Vitamin C Administration to the Critically Ill: A Systematic Review and Meta‐Analysis

19 November 2018 https://doi.org/10.1002/jpen.1471
Vitamin C, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation,
oxidative stress, and microvascular dysfunction. While observational studies have demonstrated that
critical illness is associated with low levels of vitamin C, randomized controlled trials (RCTs) of
vitamin C, alone or in combination with other antioxidants, have yielded contradicting results. We
searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials
(inception to December 2017) for RCTs comparing vitamin C, by enteral or parenteral routes, with
placebo or none, in intensive care unit (ICU) patients. Two independent reviewers assessed study
eligibility without language restrictions and abstracted data. Overall mortality was the primary
outcome; secondary outcomes were incident infections, ICU length of stay (LOS), hospital LOS, and
duration of mechanical ventilation (MV). We prespecified 5 subgroups hypothesized to benefit more
from vitamin C. Eleven randomized trials were included. When 9 RCTs (n = 1322) reporting mortality
were pooled, vitamin C was not associated with reduced risk of mortality (risk ratio [RR] 0.72, 95%
confidence interval [CI]: 0.43–1.20, P = .21). No effect was found on infections, ICU or hospital LOS,
or duration of MV. In multiple subgroup comparison, no statistically significant subgroup effects
were observed. However, we did observe a tendency towards a mortality reduction (RR 0.21; 95%
CI: 0.04–1.05; P = .06) when intravenous high‐dose vitamin C monotherapy was administered.
Current evidence does not support supplementing critically ill patients with vitamin C. A moderately
large treatment effect may exist, but further studies, particularly of monotherapy administration, are
warranted.
Vitamin C in the critically ill - indications and controversies
World J Crit Care Med. 2018 Oct 16; 7(5): 52–61.
Published online 2018 Oct 16.  doi:  10.5492/wjccm.v7.i5.52
There has recently been a surge of interest in the use of vitamin C as an adjuvant treatment for
sepsis. This interest was stimulated by the findings of a cohort study by Marik et al[64] that
administered a cocktail of vitamin C (1.5 g IV every 6 h), hydrocortisone (50 mg IV every 6 h) and
thiamine (200 mg IV every 12 h) to 47 septic patients and found a significant reduction in SOFA
scores, dependence on vasopressors, and most importantly in hospital mortality to 8.5% in the
treatment arm vs 40.4% in a historic control group. These findings were consistent with small phase I
double-blinded placebo-controlled trials suggesting the beneficial effects of vitamin C in patients
with sepsis[67]. This trial, which randomized 24 septic patients with documented hypovitaminosis C
to receive placebo, low-dose (50 mg/kg per day) or high-dose (200 mg/kg per day) parental vitamin
C for four days, found significant reductions in SOFA scores and CRP plasma levels in the vitamin C-
treated groups[67]. In another small trial of critically ill surgical patients, Zabet et al[65] reported a
significant reduction in 28 d mortality in 14 patients with septic shock who were randomized to
receive 25 mg/kg per day of ascorbic acid every 6 h for 72 h, when compared to 14 patients with
septic shock who received placebo. Despite these promising findings, there are potential safety
concerns worthy of consideration with vitamin C administration in the critically ill population. A
recent study by De Grooth et al[68] evaluated four parenteral vitamin C repletion regimens (2
g/d vs 10 g/d; bolus vs continuous infusion) administered for 48 h to critically ill patients with
multiple organ dysfunction. The patients receiving 10 g vitamin C per day had supraphysiologic
vitamin C levels and hyperoxaluria, oxalate being a metabolite of vitamin C. These findings raise
concern for an increased risk of oxalate nephropathy, as has been reported with high-dose vitamin C
administration and more prolonged administration in the noncritically ill population[68,79,80]. This
theoretical risk of oxalate nephropathy stands in contrast with the mostly reassuring data about the
safety of short-term high-dose vitamin C administration[64,65,67].
VITAMIN C IN CANCER PATIENTS
Perhaps more widely investigated than any other vitamin C-related claim is the assertion of benefit
for patients with cancer. In fact, a quick PubMed search of “ascorbic acid + cancer” yielded 4,376
items, 247 of which were clinical trials (as of May 2018).
Cancer patients have been recognized to have low vitamin C levels compared with healthy
controls[120]. In a large randomized, placebo-controlled trial, daily intake of antioxidants, vitamins
and minerals, a combination of vitamin C (120 mg/d), vitamin E, zinc, beta carotene and selenium
lowered total cancer incidence and all-cause mortality in men but not women at 7.5 years[121]. A
similar regimen of vitamin C and E supplementation with beta carotene did not, however, prevent
the formation of colon adenomas in a randomized trial of 864 patients[122]. Another study of
vitamin C and E supplementation for cancer prevention did not identify immediate or long-term
effects on the risk of total cancers, prostate cancer, or other site-specific cancers[123].
A randomized clinical trial examining different doses of vitamin C (1, 2 or 4 g/d) failed to find a dose-
response relationship or an association between serum ascorbic acid levels and mutagen sensitivity,
which has been described as a risk factor for tobacco-related epithelial cancers[124]. Despite these
clinical findings, basic science data suggest that vitamin C may have a beneficial role in cancer
progression through several different mechanisms. Vitamin C was recently found to restore Tet
methylcytosine dioxygenase 2 function, one of the most frequently mutated genes in hematopoietic
malignancies. Through this mechanism, vitamin C may block aberrant self-renewal and leukemia
progression[125]. Vitamin C also facilitates DNA oxidation in leukemia cells, rendering them more
sensitive to poly ADP ribose polymerase inhibitors[125].
In cholangiocarcinoma, SVCT2 expression levels have been shown to correlate with susceptibility to
vitamin C-induced cancer cell death in vitro and in vivo[126]. In separate experiments, Vitamin C has
been shown to increase methotrexate-mediated hepatocellular carcinoma cell death[127].
Furthermore, vitamin C enhances the effectiveness of radiation therapy for glioblastoma and
gemcitabine/epigallocatechin-3-gallate treatment for mesothelioma[128,129]. These findings are in
contrast to data showing that vitamin C interferes with chemotherapy drugs such as doxorubicin,
methotrexate, and cisplatin[128-131]. Moreover, vitamin C may enhance the growth of some
cancers. For example, plasmocytoma cell growth is dependent on the presence of vitamin C[132].
Vitamin C exposure showed differential effects in an in vitro model of colony-forming bone marrow
cell growth in patients with myelodysplastic syndrome. In this model, vitamin C responsiveness (both
growth enhancement or inhibition) was associated with shorter survival when compared to patients
with no response to vitamin C[133]. Adding to this complex picture is data derived from in vitro work
that examined the response of HL-60 cells from an acute myeloid leukemia cell line to vitamin C.
Vitamin C administration decreased oxidative stress and thus protected HL-60 cells from H 2O2-
induced cell death[134].
Curiously, high-dose vitamin C (0.5-5 mmol/L) has also been shown to increase the procoagulant
properties of freshly isolated red blood cells via externalization of phophatidylserine, a mechanism
known to lead to thrombus formation. Interestingly, this effect was more pronounced in red blood
cells from cancer patients and could be confirmed in a rat model of thrombus formation[135].
In one study in terminal cancer patients, vitamin C was associated with increased quality-of-life and
survival[116]. In contrast, in two double-blinded randomized controlled trials that included patients
with advanced cancers (stomach, colon, pancreas, lung, breast and others), vitamin C (10 g/d) did
not improve survival[136,137].
Given the complexities of cancer biology and vitamin C, the risks and benefits of initiating high-dose
vitamin C therapy in critically ill oncology patients should be carefully weighed and discussed with
the oncology consultant.
CONCLUSION
Vitamin C is once again a focus of intense interest with respect to its role in the treatment of
critically ill patients. Evidence suggests that vitamin C administration may have a variety of beneficial
effects in patients undergoing cardiac surgical procedures, during resuscitation with acute burn
injury, for the treatment of sepsis, in reducing pain, and in the treatment of cancer. While many
questions have yet to be answered, there is little data to suggest that short-term high-dose vitamin C
would elicit major harm, except for the risk of oxalate nephropathy. In fact, evidence suggests that
short-term high-dose vitamin C in selected patients may improve hemodynamic parameters,
decrease fluid resuscitation requirements, reduce the incidence of perioperative atrial fibrillation,
improve pain and potentially reduce sepsis-associated mortality. We eagerly await additions to the
growing body of evidence that examine the role of vitamin C administration for improving outcomes
for our sickest patients.

NOVEMBER 25, 2019

CITRIS-ALI: Vitamin C in Patients with Sepsis and Severe Acute Respiratory Failure
Author Conclusion: “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.”
Clinical Take Home Point: In this study of high dose vitamin C in patients with sepsis and ARDS, there
was not statistical difference in the primary outcomes of change in modified SOFA score at 96hrs,
plasma biomarkers of inflammation (CRP), nor plasma biomarkers of vascular injury
(thrombomodulin ). Normally, I don’t get too excited about secondary outcomes, however in a study
of sick patients with sepsis induced ARDS, with high mortality rates, maybe we should consider using
vitamin C. With no adverse events and how inexpensive vitamin C is, one could argue that this is an
option we should try (kitchen sink mentality). On the other hand, with 46 secondary outcomes, it is
possible that the mortality benefit was from chance alone. Regardless of which side of this debate
you fall on, one thing is certain…evaluation of vitamin C in a larger trial seems to be warranted
looking at multiple dosing and timing strategies.

Effects of different  ascorbic acid  doses on the mortality of critically ill patients: a meta-analysis
Ann Intensive Care.  2019 May 20;9(1):58. doi: 10.1186/s13613-019-0532-9.
Abstract
BACKGROUND:
Low levels of ascorbic acid (AA) have been detected in critically ill patients in which AA
supplementation leads to promising outcomes. However, the ability of AA to reduce mortality in
critically ill patients remains controversial. In this study, we have performed a meta-analysis to
evaluate the effects of AA dose on the mortality of critically ill adults.
METHODS:
Electronic databases were searched for trials in which AA had been intravenously administered to
critically ill patients regardless of the dose or the co-administration of antioxidant agents. The
predefined primary outcome included all-cause mortality at final follow-up.
RESULTS:
The included trials enrolled a total of 1210 patients. Intravenous (IV) AA doses of 3-10 g/d reduced
the mortality of critically ill patients (OR 0.25; 95% CI (0.14-0.46); p < 0.001; I 2 = 0.0%), while low (< 3
g/d) and high AA doses (≥ 10 g/d) had no effect (OR 1.44; 95% CI (0.79-2.61); p = 0.234; I 2 = 0.0%
versus OR 1.12; 95% CI (0.62-2.03); p = 0.700; I 2 = 0.0%). AA was associated with a decreased
duration of vasopressor support and mechanical ventilation, but did not influence fluid requirement
or urine output during the first 24 h of admission. The number of patients suffering from acute
kidney injury and the length of intensive care unit or hospital stays were also unaffected by the AA.
CONCLUSION:
Intravenous AA reduces the duration of vasopressor support and mechanical ventilation; 3-10 g AA
results in lower overall mortality rates. Given the limitations of the primary literature, further studies
are required to fully clarify the effectiveness of AA during the management of critically ill patients.

Curr Opin Crit Care.  2019 Aug;25(4):329-333. doi: 10.1097/MCC.0000000000000622.

Safety of  vitamin C  in sepsis: a neglected topic.
Abstract
PURPOSE OF REVIEW:
Although vitamin C is essentially a nontoxic vitamin; however, it is important to be aware regarding
the safety of high doses before the wide clinical use.
RECENT FINDINGS:
Minor side effects of vitamin C have been reported, many being reported in earlier
studies. High doses of vitamin C (up to 1.5 g/kg three times a week as intravenously) were safe in
cancer patients with normal renal function and perfect glucose-6-phosphate dehydrogenase activity.
As the dose and duration of administration of vitamin C in sepsis are lower and shorter than those
used in cancer patients, it seems that it is relatively safe for this population. In ongoing trials, safety
of high doses of vitamin C is considered.
SUMMARY:
Data regarding the safety of high doses of vitamin C are scant. Until more data become available,
caution should be applied in the use of high doses of vitamin C in patients with hemochromatosis,
glucose-6-phosphate dehydrogenase deficiency, renal dysfunction, kidney stone, oxaluria, and
pediatrics.

Vitamin C  for the critically ill: Is the evidence strong enough?

Abstract
Vitamin C exhibits interesting properties in the context of critical illness, with benefits described in
neurologic, cardiovascular, renal, and hematologic systems, both in in vitro and in animal models.
Through direct effects on bacterial replication, immunomodulation, and antioxidant reserve of the
organism, vitamin C directly affects the pathophysiological process of sepsis, trauma, burn, and
systemic inflammation. Even if several observational trials have linked vitamin C deficiency to worse
outcomes, the evidence is not such as to provide us with a distinction between causality effects or
simple epiphenomenon, and the current focus is on interventional trials. Pharmacokinetic data
suggest that a minimal supplementation of 3 g/d intravenously is required to restore normal serum
values in critically ill patients with known deficiency. According to these data, only five trials,
including a retrospective analysis, studied pharmacologic dose: three as an antioxidant cocktail and
two as monotherapy. The largest trial, conducted in 2002, reported reduced incidence of multiorgan
failure and duration of mechanical ventilation. Recently a retrospective analysis reported impressive
results after administration of vitamin C, thiamine, and hydrocortisone. The two most recent trials
reported improved clinical outcomes, including improved mortality, but contained significant
methodological limitations. A recent systematic review did not find clinical benefits with the most-
studied low-dose oral supplementation, potentially because of suboptimal or insufficient repletion.
Current guidelines do not support the administration of high-dose vitamin C in critically ill patients.
Future larger trials are required to support any therapy, but the low cost and safety profile can
justify supplementation in the meantime. Metabolomics study will further help understand
biological effect.

JPEN J Parenter Enteral Nutr.  2019 Mar;43(3):335-346. doi: 10.1002/jpen.1471. Epub 2018 Nov 19.
Vitamin C  Administration to the Critically Ill: A Systematic Review and Meta-Analysis.
Abstract
Vitamin C, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation,
oxidative stress, and microvascular dysfunction. While observational studies have demonstrated that
critical illness is associated with low levels of vitamin C, randomized controlled trials (RCTs)
of vitamin C, alone or in combination with other antioxidants, have yielded contradicting results. We
searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials
(inception to December 2017) for RCTs comparing vitamin C, by enteral or parenteral routes, with
placebo or none, in intensive care unit (ICU) patients. Two independent reviewers assessed study
eligibility without language restrictions and abstracted data. Overall mortality was the primary
outcome; secondary outcomes were incident infections, ICU length of stay (LOS), hospital LOS, and
duration of mechanical ventilation (MV). We prespecified 5 subgroups hypothesized to benefit more
from vitamin C. Eleven randomized trials were included. When 9 RCTs (n = 1322) reporting mortality
were pooled, vitamin C was not associated with reduced risk of mortality (risk ratio [RR] 0.72, 95%
confidence interval [CI]: 0.43-1.20, P = .21). No effect was found on infections, ICU or hospital LOS, or
duration of MV. In multiple subgroup comparison, no statistically significant subgroup effects were
observed. However, we did observe a tendency towards a mortality reduction (RR 0.21; 95% CI:
0.04-1.05; P = .06) when intravenous high-dose vitamin C monotherapy was administered. Current
evidence does not support supplementing critically ill patients with vitamin C. A moderately large
treatment effect may exist, but further studies, particularly of monotherapy administration, are
warranted.

Intravenous  vitamin C  as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory

distress syndrome.
Abstract
We report a case of virus-induced acute respiratory distress syndrome (ARDS) treated with
parenteral vitamin C in a patient testing positive for enterovirus/rhinovirus on viral screening. This
report outlines the first use of high dose intravenous vitamin C as an interventional therapy for
ARDS, resulting from enterovirus/rhinovirus respiratory infection. From very significant preclinical
research performed at Virginia Commonwealth University with vitamin C and with the very positive
results of a previously performed phase I safety trial infusing high dose vitamin C intravenously into
patients with severe sepsis, we reasoned that infusing identical dosing to a patient with ARDS from
viral infection would be therapeutic. We report here the case of a 20-year-old, previously healthy,
female who contracted respiratory enterovirus/rhinovirus infection that led to acute lung injury and
rapidly to ARDS. She contracted the infection in central Italy while on an 8-d spring break from
college. During a return flight to the United States, she developed increasing dyspnea and
hypoxemia that rapidly developed into acute lung injury that led to ARDS. When support with
mechanical ventilation failed, extracorporeal membrane oxygenation (ECMO) was initiated. Twelve
hours following ECMO initiation, high dose intravenous vitamin C was begun. The patient's recovery
was rapid. ECMO and mechanical ventilation were discontinued by day-7 and the patient recovered
with no long-term ARDS sequelae. Infusing high dose intravenous vitamin C into this patient with
virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-
ARDS fibroproliferative sequelae. Intravenous vitamin C as a treatment for ARDS may open a new
era of therapy for ARDS from many causes.