Vitamin C for Sepsis

Sepsis happens when your body has an unusually severe response to an infection and it
is also sometimes called septicemia. During sepsis, your immune system, which protects you
against infections, produces a large amount of chemicals into your blood which causes
extensive inflammation that can harm the organs. The clots decrease blood flow to your limbs
and internal organs, preventing them from receiving the nutrition and oxygen they require
(Dunkin, 2020). The Sepsis may also progress into a septic shock where the body may
dramatically drop in blood pressure and may lead to a severe organ problem and death. This is
why sepsis is a potentially life-threatening condition. Sepsis is also has become the third
greatest cause of death in hospitals, costing almost 60 billion each year, and even surviving
patients are at risk of poor physical condition, mood, and cognitive results, resulting in a lower
quality of life (Marik, 2018).

A deficiency in Vitamin C is common in patients with sepsis. The lower vitamin C levels
are associated with a higher likelihood of organ failure. This is caused by the explosive cytokine
release present in sepsis, which interferes with the cellular regulation of vitamin C absorption. In
addition, during this overwhelming disease state of oxidative stress and increased reactive
oxygen species (ROS) production, there is increased vitamin C consumption by the somatic
cells which contributes to the vitamin depletion in sepsis (Kashiouris et al., 2019).

Most animal species can synthesize vitamin C in the kidneys or in the liver, humans
however do not have the ability to synthesize vitamin C in their body. Vitamin C plays a role in
mediating inflammation through antioxidant activity, and is an important co-factor/co-substrate
for the synthesis, of endogenous adrenaline cortisol, and vasopressin. Thus some studies
conclude supplementation of vitamin C can be a treatment for patients with sepsis. Vitamin C
protects against endothelial barrier degradation and inhibits neutrophil-induced lipid oxidation
during sepsis. As a result, early intravenous supplementation for sepsis would be advantageous
in terms of avoiding microcirculation loss and lipid oxidation. (Kashiouris et al., 2019; Shin et al.,
2019).

Different clinical trials have been conducted on vitamin C as a treatment for sepsis. The
first study was published in 1986 where 16 patients who have sepsis-induced acute respiratory
distress syndrome (ARDS) was treated with intravenous vitamin C (1000 mg IV every 6 hours)
plus antioxidants (N-acetylcysteine, selenium, and vitamin E) versus 16 ARDS patients who
received the standard care at that time or is the control group. The result shows that there is a
dramatic reduction in the mortality in vitamin C group than the standard care group (Sawyer et
al., 1989). In 2014, a phase 1 trial for intravenous ascorbic acid in patients with severe sepsis
has shown that plasma vitamin C levels of patients with severe sepsis are low and that the high-
dose intravenous vitamin C (HDIVC) administration had a dose-dependent effect in the
prevention of multi-organ failure. Patients who received a total of 200 mg/kg/day of HDIVC for 4
days (administered in 50 mg/kg/dose, every 6 h), had significantly lower SOFA scores than
placebo, and even lower scores than the patients who received lower-doses of IV vitamin C (50
mg/kg/day administered at 12.5 mg/kg/dose, every 6 h for 4 days). As demonstrated, reduction
score was remarkable in patients that are receiving high dose of ascorbic acid infusion (Fowler
et al., 2014).

Another study in 2016 where a before-after study of severe sepsis and septic shock
when treated with vitamin C is conducted. Patients who received hydrocortisone (50 mg IV
every 6 h for 7 days or until ICU discharge), thiamine (200 mg IV every 12 h for 4 days or until
ICU discharge) and HDIVC (6000 mg/day, in 4 divided doses for 4 days or until ICU discharge)
to control are compared and shows that the mortality of sepsis are decreased to those who are
have taken the triple-teraphy compare to the control group (Marik at al., 2016).

The CITRIS-ALI trial, the largest trial completed on vitamin C to date was published in
2019. It is a multicenter, randomized, double0blinded trial that included 167 patients that has
sepsis and ARDS. Participants were randomized to receive 50 mg/kg every 6 h of HDIVC for 4
days versus placebo. After the study is completed in 60 days there is no significant difference
between the vitamin C group and the placebo group. This is possibly because of the advanced
stages of sepsis before the development of ARDS. However, preclinical research in early sepsis
revealed that vitamin C prevented sepsis-induced cytokine surges that activate and sequester
neutrophils in lung, thus damaging alveolar capillaries. 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. In addition, vitamin
C prevented neutrophil extracellular trap formation, a biological event in activated neutrophils
that promotes vascular injury. It is also notable that a significant reduction in the 28 day mortality
in the vitamin C group (Fowler et al., 2019).

In terms of adverse events, HDIVC was found to be safe and has no significant side-
effects that are recorded. Almost all of the studies mention above has no adverse events that
have happened. However, there is one proposed side effect of HDIVC which is an increased
propensity for oxalate kidney stone production, but it has never been happened in any clinical
trials to date.

In conclusion, different laboratory, animal, and clinical studies is building a supporting

evidences for HDIVC as a treatment for sepsis. The intravenous administration of the vitamin C
is a promising treatment for sepsis as most of the studies decreases the mortality and organ
failure that happens during sepsis. Administration of vitamin C intravenously is also much more
preferable rather than oral administration of vitamin C as it shows a higher plasma concentration
of ascorbate in the body. Thus, most of the studies of IV administration are successful. Further
studies for other roles of the vitamin C in sepsis aside from reducing organ failure may be
investigated.
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