REVIEW

CURRENT
OPINION Vitamin C supplementation in the critically
ill patient
Mette M. Berger a and Heleen M. Oudemans-van Straaten b

Purpose of review
Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important
player of the endogenous antioxidant defense. Low plasma levels are very common in critical care patients
and may reflect severe deficiency states.
Recent findings
Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells
(preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of
the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-
induced intracellular adhesion molecule expression, which triggers leukocyte stickiness and slugging.
Clinical trials in sepsis, trauma and major burns testing high-dose vitamin C show clinical benefit.
Restoration of normal plasma levels in inflammatory patients requires the administration of 3 g/day for
several days, which is 30 times the daily recommended dose.
Summary
The recent research on the modulation of oxidative stress and endothelial protection offer interesting
therapeutic perspectives, based on the biochemical evidence, with limited or even absent side-effects.
Keywords
antioxidant, ascorbic acid, endothelial dysfunction, inflammation, supplementation

INTRODUCTION higher than in plasma, with highest concentrations

Critically ill patients suffer from multiple organ in leukocytes and neurons. Intracellular ascorbic
failure (MOF) because of sepsis or ischemia/reperfu- acid protects cells against oxidative damage and
sion. Part of the injury is mediated by reactive oxy- participates in numerous cellular functions.
gen species (ROS). Mitochondrial respiration is an Vitamin C deficiency, classically known as
important source of ROS, which act as signaling scurvy, is a clinical syndrome with lethargy, peri-
molecules and are produced for phagocytosis within follicular petechiae, erythema, gingivitis, bleeding,
&
the phagosome [1 ]. However, when the normally impaired wound healing and depressed immunity,
contained production is overwhelming, ROS can conditions rarely observed in the ICU. Important
cause damage to lipids, proteins and DNA. However, questions are why plasma concentrations are low,
ROS also induce antioxidant responses that may whether this reflects intracellular deficiency,
protect against further damage, strategies called whether deficiency is harmful and whether supple-
preconditioning and postconditioning [2,3 ]. Thus,
&
mentation can improve clinical outcome. The
the balance between timing and intensity of ROS present contribution aims to update the growing
production and scavenging seems critical. knowledge about the crucial role of vitamin C, its
Vitamin C is a water-soluble antioxidant circu-
lating in plasma. It is taken up by the intestine via a
Adult Intensive Care and Burns, University Hospital CHUV, Lausanne,
the sodium-dependent vitamin C transporter Switzerland and bDepartment of Intensive Care, VU University Medical
(SVCT1), freely filtered by the glomerulus and reab- Center, Amsterdam, the Netherlands
sorbed in the proximal tubule via the SVCT1 trans- Correspondence to Mette M. Berger, Service of Adult Intensive Care and
porter. In case of deficiency, urinary excretion is Burns, CHUV BH 08.612, Rue du Bugnon 46, 1011 Lausanne, Switzer-
minimal. Subsequent uptake into the cells occurs land. Tel +41 21 31 42 095; e-mail: [email protected]
&
via the SVCT2 transporter [4 ]. This active transport Curr Opin Clin Nutr Metab Care 2015, 18:193–201
provides intracellular concentrations manifold DOI:10.1097/MCO.0000000000000148

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Nutrition and the intensive care unit

a-tocopherol (X in Fig. 1). It does so by donating an

KEY POINTS electron and generating the ascorbyl radical, which
 Vitamin C deficiency is highly prevalent during critical is pro-oxidant in itself, but has replaced a potentially
illness, with very low plasma levels. more damaging radical. Furthermore, the ascorbate
radical, being relatively stable and unreactive with
 Perioperative ascorbic acid supplementation belongs to other molecules because of the position of its free
the antioxidant strategies of postoperative atrial
electron, easily reacts with itself. Dismutation of two
fibrillation in cardiac surgery.
ascorbyl radicals produces one molecule of ascor-
 Endothelial dysfunction is mediated by the oxidant bate and one molecule of dehydroascorbate (DHA),
mechanisms that ascorbic acid is able to attenuate and &
which is rapidly further reduced (Fig. 1) [4 ]. If this
counteract, making it as serious candidate for does not occur, the molecule is lost as antioxidant.
adjunctive treatments in sepsis and other inflammatory
Ascorbate has pro-oxidant properties as well. It
conditions.
can generate very low levels of O2
and reduce
 High-dose ascorbic acid has been used in clinical trials catalytic metals such as Fe2þ and Cu2þ. In the pres-
in several diseases with beneficial effects and no side- ence of ascorbate, these metals can initiate radical
effects. chain oxidations. Ascorbate could, therefore, be
 Reliable point-of-care determination of vitamin C is detrimental in case of iron overload. In general, in
highly desirable, but still not available. low concentrations ascorbate is pro-oxidant,
whereas high concentrations are needed for its
antioxidant properties. These high concentrations
inhibit the initiated radical chain reactions [5].
deficiency and its adjuvant treatment potential Endothelial dysfunction is a manifestation of
during critical illness. sepsis and ischemia/reperfusion injury. It is charac-
terized by a diminished response to both endothelial-
dependent vasodilators and to vasoconstrictors, and
ANTIOXIDANT AND PRO-OXIDANT a loss of barrier function. Endothelial dysfunction is
PROPERTIES triggered by the activation of NADPH oxidase or
Vitamin C scavenges ROS such as superoxide (O2
) nicotinamide adenine dinucleotide oxidase (NOX),
and peroxynitrite (ONOO
) in plasma and cells, which generates O2
from oxygen, and is associated
and thereby prevents damage to proteins, lipids with decreased bioavailability of nitric oxide. The
and DNA. Ascorbate can further repair other production of nitric oxide is decreased because O2

oxidized scavengers such as glutathione, urate and oxidizes tetrahydrobiopterin (BH4), the cofactor of

Sepsis/IR Mitochondrial respiration

NOX ↑

O2– H2O2
ONOO– Fe2+
Fe3+
X• XH

GSH
AscH– NADPH Asc•– + Asc•–

Dismutation

GSH
+
NADPH DHA

FIGURE 1. Oxidative metabolism of ascorbate. Sepsis and ischemia/reperfusion (IR) generate reactive oxygen species (ROS)
by the activation of NADPH oxidase (NOX) and mitochondrial respiration. Ascorbate (AscH
) scavenges free radicals from
peroxynitrite, superoxide or other damaging ROS or oxidized antioxidants (X
), thereby generating the ascorbyl radical
(Asc
), which is far less damaging than X
. Dismutation of two Asc
molecules produces one molecule of ascorbate and
one molecule of dehydroascorbate (DHA). DHA is rapidly reduced by glutathione or by NOX-dependent reductases.

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 Vitamin C in critical care Berger and Oudemans-van Straaten

nitric oxide synthetase (NOS). When oxidized BH4 which triggers leukocyte stickiness and slugging.
(BH2) binds to endothelial NOS (eNOS), the enzyme In combination with a-tocopherol, ascorbate
becomes uncoupled and produces O2
instead of additionally inhibits several apoptotic pathways
nitric oxide. Furthermore, O2
activates inducible
& &
(summarized in [4 ,6 ]).
NOS (iNOS) and reacts with nitric oxide to form The recycling of BH4 by ascorbate has additional
ONOO
, a severely damaging ROS (Fig. 2). ONOO
important consequences, because other enzymes
&
can also damage the endothelial barrier by BH4 inac- have BH4 as cofactor as well [4 ]. BH4 maintains
tivation and dephosphorylation of occludin (a com- catalytic iron in the ferrous form. Iron-dependent
ponent of the tight junctions). enzymes are part of the norepinephrine and seroto-
Ascorbate inhibits NOX activation, scavenges nin synthetic pathways, and play a role in lipid
O2
and ONOO
, and thereby prevents occludin metabolism. Vitamin C has long been known as an
dephosphorylation and loosening of the tight junc- essential cofactor in the hydroxylation of enzymes
&
tions [6 ]. Ascorbate also recovers BH4 from its oxi- involved in type IV collagen hydroxylation. Ascor-
dized form BH2. As BH4 is the cofactor of eNOS, bate also plays a role in oxidative protein folding, an
ascorbate increases nitric oxide availability, thereby essential step in collagen synthesis [8]. Type IV col-
maintaining microvascular perfusion and endo- lagen is part of the basement membrane of blood
&
thelial barrier function [4 ] (Fig. 2). Ascorbate also vessels and essential for endothelial adhesion and
recycles a-tocopherol and as such protects against wound healing. Hence, incomplete collagen IV
lipid peroxidation [7]. Ascorbate can further leads to scurvy and impairs wound healing. Finally,
improve microcirculatory flow impairment by vitamin C plays a role in carnitine biosynthesis.
inhibiting tumor-necrosis-factor-induced intra- Neurons in the central nervous system (CNS)
cellular adhesion molecule (ICAM) expression, have high rates of oxidative metabolism and

I/R TNF ICAM expression ↑ Leukocyte slugging ↓

Sepsis A
Mitochondrial permeability ↑
A
Apoptosis
A NOX act. ↑ BH4 eNOS

iNOS ↑ A Barrier ↑
A O2–
NO cGMP Vasodilation
NO BH2

O2– ONOO–
BH3
A ONOO– A A

A eNOS uncoupling
Vasoreactivity ↓
PP2A act. ↑ eNOS deP
NO depletion
Occludin-P Occludin

Loosening tight junctions

FIGURE 2. Antioxidant properties of ascorbate. Ascorbate (A) inhibits the formation of superoxide (O2
) and peroxynitrite
(OONO
) by inhibiting the activation of NADPH oxidase (NOX) which produces superoxide (O2
) and inhibiting inducible
nitric oxide (iNOS) mRNA expression, preventing the abundant production of nitric oxide (NO) which generates OONO
in
the presence of O2
. Ascorbate protects pathological vasoconstriction and loss of endothelial barrier by inhibiting
tetrahydrobiopterin (BH4) oxidation, the cofactor of endothelial nitric oxide synthetase (eNOS), thereby preventing eNO
depletion and eNOS uncoupling, which generates O2
. Ascorbate protects against vascular leakage by inhibiting protein
phosphatase 2A (PP2A) activation, which dephosphorylates occludin. Phosphorylated occludin is crucial for the maintenance
of tight junctions. Ascorbate protects against mitochondrial permeability transition which initiates apoptotic pathways.
Ascorbate inhibits tumor necrosis factor (TNF)-induced intracellular adhesion molecule (ICAM) expression, which increases
stickiness and slugging of leukocytes in the microcirculation.

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Nutrition and the intensive care unit

contain some of the highest concentrations of ascor- ill patients have low vitamin C plasma concen-
& &&
bate. Intracellular ascorbate serves several functions trations [6 ,17 ]. After cardiac surgery, a rapid
in the CNS, including antioxidant protection, decline is seen during cardiopulmonary bypass and
peptide amidation, myelin formation, synaptic prolonged depletion may occur [18]. Low plasma
potentiation, catecholamine synthesis and protec- concentrations are associated with inflammation,
tion against glutamate toxicity. Ascorbate decreases severity of organ failure and mortality [19]. Several
infarct size in experimental stroke [9]. studies report the development of severe ascorbic
acid deficiency with scurvy-like symptoms during
the systemic inflammatory response syndrome with
IMMUNE FUNCTION capillary leakage associated with interleukin-2
During sepsis, polymorphonuclear neutrophils fight immunotherapy, whereas other vitamins were not
pathogens by phagocytosis, by exposure to ROS in deficient [12].
phagolysosomes, by degranulation with release of Animal studies have shown that after the induc-
antibacterial peptides and proteases, and by pro- tion of sepsis, intracellular ascorbate plasma con-
duction of cytokines and other inflammatory centrations rapidly decline in plasma, lymphocytes
mediators [10]. A novel death pathway for pathogen and macrophages, muscle and myocardium despite
&
killing includes the formation of neutrophil extra- dietary supplementation (summarized in [6 ]). An
cellular traps (NETs). NETs collect proteases and explanation could be high leukocyte turnover,
antimicrobial proteins in the neighborhood of because intracellular ascorbate concentrations in
trapped pathogens. Excessive NET formation in monocytes and granulocytes are 25 and 80 times
sepsis can, however, damage host tissues such as higher, respectively than in plasma. Low plasma
the lung [11]. concentration may also be due to reduced recycling
Vitamin C can boost the immune response via of DHA back to ascorbate because of an altered redox
& & &
several pathways (summarized in [4 ,6 ,12,13 ]). state or glutathione deficiency as a result of oxi-
&
Deficiency is associated with impaired cell-mediated dative stress (Fig. 1) [4 ]. That low plasma concen-
immunity, for example, suppressed T cytotoxic trations reflect real deficiency and low intracellular
responses, natural killer activity, delayed-type concentrations is supported by the finding that
hypersensitivity and bacterial clearance. Vitamin urinary concentrations initially remain low despite
C improves chemotaxis, stimulates interferon pro- high-dose intravenous supplementation, and only
duction, enhances motility, neutrophil phagocytic increase after a couple of days when plasma con-
capacity and oxidative killing, and supports centrations increase above 30 mmol/l [20,21]. This
lymphocyte proliferation. In dilute fecal samples, suggests that intracellular stores are replenished.
ascorbate has been reported to inhibit the replica- That vitamin C deficiency has metabolic con-
tion of bacteria and to lower bacterial counts in sequences is recently shown in otherwise healthy
&
blood during bacterial peritonitis in mice [13 ,14]. young guinea pigs. Like humans, guinea pigs lack
The bacteriostatic effects may be mediated by the the capacity to synthesize vitamin C. Induction of
formation of hydrogen peroxide (H2O2) (Fig. 2). A depletion by dietary deprivation caused a decline
recent study shows attenuation of NET formation in in plasma BH4 concentration and an increase in
the serum of septic vitamin-C-sufficient mice and in BH2/BH4 ratio and DHA [22]. Furthermore, in
vitamin-C-deficient mice treated with ascorbic acid animals, supplementation of high-dose vitamin C
[15,16]. Studies in septic animals have shown that prevented or restored microvascular flow impair-
supplementation of high-dose vitamin C dimin- ment, vascular responsiveness to vasoconstrictors,
ished organ damage or improved survival, whereas preserved endothelial barrier and prevented
&
in other studies mortality was higher in vitamin-C- apoptosis [6 ].
&
deficient animals compared with controls [6 ].

PERSISTENCE OF DEFICIENCY CASE

LOW PLASMA VITAMIN C REPORTS
CONCENTRATION Isolated case reports of life-threatening deficiencies
Vitamin C plasma concentrations depend on absorp- continue to be published such as the case of a 56-
tion and distribution volume, glomerular filtration, year-old woman with sepsis on a background of
tubular reabsorption and urinary excretion, and rheumatoid arthritis and steroid use manifesting
intracellular uptake and consumption. Plasma con- with overt clinical features of scurvy [23]. Vitamin
centration can be low because of insufficient intake, C replacement resulted in rapid resolution of the
chronic or acute ‘consumption’ in the setting of symptoms. But the clinical course may be fatal: a
increased oxidative stress or increased loss. Critically 79-year-old man was brought to the emergency

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 Vitamin C in critical care Berger and Oudemans-van Straaten

department because of a progressive onset of response causing peroxidation of lipid, protein

confusion associated with marked lethargy, mild and or DNA. The observed depletion of ascorbate
hypotension and tachycardia suggesting sepsis. He in sepsis and its established underlying pathophysi-
presented with a coma of rapid onset, which required ology provide sufficient evidence to support the
emergent intubation [24]. Over that same night, he clinical trials of parenteral ascorbate as an adjuvant
&
developed MOF and irreversible shock. Postmortem therapy [30 ]. A Brazilian study [31] including 23
laboratory results showed extreme low ascorbic acid ICU patients compared a standard diet to additional
plasma concentration 3.0 mmol/l. These cases show daily oral antioxidant vitamin supplementation
that in the presence of a sepsis syndrome and likely (10 000 IU retinol, 400 mg a-tocopherol and
underfeeding, a high degree of suspicion should be 600 mg ascorbic acid). The authors observed signifi-
maintained regarding potential severe ascorbic cantly lower serum concentrations of malondialde-
acid deficiencies. hyde, a marker of lipid peroxidation, and higher
a-tocopherol in the antioxidant group, but no
CLINICAL INTERVENTION STUDIES significant impact on the clinical parameters. How-
Most of the published clinical trials have included ever, an oral dose of 600 mg/day is insufficient to
patient cohorts with an important inflammatory restore plasma concentrations, as has recently been
response. The present article focuses on the trials shown in a multicenter trial on immune-enhanced
published after 2010: anterior trials were recently enteral nutrition (electronic supplement) [32]. After
&
reviewed [6 ]. 8 days, plasma concentrations were increased versus
control, but still subnormal (median 23.0 versus
Cardiac surgery and coronary percutaneous 9.7 mmol/l).
coronary interventions A recent, phase I trial including 24 medical
&&
The cardiac-surgery-induced inflammatory response patients with severe sepsis [17 ] compared two differ-
is typically associated with a high rate of postoper- ent doses of intravenous ascorbic acid: 50 mg/kg/24 h
ative atrial fibrillation (POAF). Several strategies aim- (3.75 g in a 75 kg patient), 200 mg/kg/24 h (15 g in a
ing to control oxidative stress [25] have been 75 kg patient) to placebo. Patients receiving ascorbic
performed to prevent this complication. Evidence acid exhibited prompt reductions in Sequential
supports the molecular basis for a novel pharmaco- Organ Failure Assessment scores versus no reduction
logical strategy using antioxidant vitamins and n-3 in placebo patients. Ascorbic acid significantly
polyunsaturated fatty acids for cardioprotection in reduced the proinflammatory biomarkers C-reactive
clinical settings that are associated with ischemia and protein and procalcitonin. This study opens import-
reperfusion, such as POAF and percutaneous coron- ant therapeutic perspectives.
ary intervention following acute myocardial infarc-
tion [26]. The results of these trials are variable and
somewhat conflicting. MAJOR TRAUMA AND BURNS
A meta-analysis [27] including 5 trials (567 Major trauma and burns are associated with marked
patients) testing prophylactic antioxidants (gener- inflammation, oxidative stress and ascorbic acid
&
ally intravenous ascorbic acid with or without depletion [6 ]. A careful metabolic repletion study
a-tocopherol) showed a significant reduction of was conducted in 14 trauma patients exhibiting low
the incidence of POAF [odds ratio (OR) 0.43, 95% plasma levels on admission [21]. The repletion of
confidence interval (CI) 0.21–0.89], all-cause plasma ascorbic acid was shown to require supra-
arrhythmia (OR 0.54, 95% CI 0.29–0.99) and ICU physiological doses of 3 g/day for 3–6 days to obtain
and hospital stay compared with controls. Another pool filling early in the postinjury period.
study in 185 coronary artery bypass graft surgery An older, randomized, placebo-controlled study
patients not included in the meta-analysis found, including 205 ICU cardiac surgery and trauma
however, no protection against POAF. The study patients and comparing a 5-day delivery of a com-
used ascorbic acid orally and in a lower dose [28]. bination of selenium, zinc, ascorbic acid (1.1 g) and
During conventional angioplasty, ascorbate thiamine, that is, doses 5–10 times the recom-
attenuated platelet CD40L upregulation [29]. The mended dose for parenteral nutrition versus con-
same group had already shown that 1 g of intra- trols who received 500 mg vitamin C per day [33],
venous ascorbic acid could improve myocardial per- found a reduction of the inflammatory response
fusion after angioplasty. along with a reduction of the hospital stay in the
trauma patients. In a before-and-after trial including
Sepsis 4294 ICU trauma patients, a high-dose antioxidant
Critically ill patients and particularly patients with supplementation protocol (200 mg selenium, 3 g
sepsis generally exhibit an intense inflammatory a-tocopherol and 3 g ascorbic acid per day) reduced

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Nutrition and the intensive care unit

the duration of respiratory failure and ventilator such therapies may require ICU, and specialists
dependence, abdominal wall complications, abdo- should be aware of this therapeutic option.
minal compartment syndrome and surgical site
infections [34]. Another randomized trial including
595 trauma patients requiring mechanical venti- Prevention of contrast-induced acute kidney
lation investigating a combination of 3 g a-toco- injury
pherol and 3 g ascorbic acid per day [35] showed a The kidney sustains a massive free-radical aggression
reduction in MOF with a relative risk of 0.43 (95% CI during injections of radiographic contrast and its
0.19–0.96), and a shorter duration of mechanical prevention is really of clinical importance, consid-
ventilation and length of ICU stay. ering the potentially severe health consequences of
The early phase of burns is characterized by this injury. A recent meta-analysis including nine
massive capillary leak and endothelial dysfunction trials (1536 patients) found that vitamin C reduced
causing shock and organ failure. Very low plasma the risk of contrast-induced acute kidney injury
&&
levels are observed early on. Resuscitation of (CI-AKI) by one-third [42 ]. Patients receiving
burn victims with very high-dose ascorbic acid ascorbic acid had 33% less risk of CI-AKI compared
(66 mg/kg/h for 24 h) was reported in Japan in the with placebo or an alternate pharmacological treat-
year 2000 [36] and has been verified in an animal ment (P ¼ 0.034). A later study (n ¼ 81) found no
model [37]. Benefits include reduction in fluid reduction of acute kidney injury (AKI), but signifi-
requirements, resulting in less tissue edema and cantly less worsening of renal function with ascorbic
body weight gain, and less respiratory impairment acid [43].
with shorter time on mechanical ventilation.
Despite these results, few burn centers resuscitate
patients with vitamin C in fear that it may increase Renal replacement therapy
the risk of renal failure. A retrospective review of 40 Continuous renal replacement is an established
patients with greater than 20% total body surface cause of water-soluble micronutrient losses [44].
area between 2007 and 2009 was performed [38]. Deplete vitamin C stores have been repeatedly
Vitamin C decreased fluid requirements and shown [45], as this water-soluble vitamin freely
increased urine output during resuscitation after flows through the filters. However, only one old
thermal injury. Although this study did not find a study measured vitamin C loss, about 68 mg/day
difference in outcomes, it demonstrates that high- [46]. Patients on intermittent hemodiafiltration lose
dose ascorbic acid can be safely used without an about 66 mg (8–230 mg) per session and plasma
increased risk of renal failure or other side-effects concentrations decrease by 40% during a 3-h session
[38] [47]. Although lower vitamin C concentrations pre-
dict (non)fatal cardiac complications [47], there are
as yet no randomized supplementation trials eval-
Bone marrow transplant uating clinical outcomes. However, randomized
In hematopoietic stem cell transplantation, ascorbic studies found a reduction of inflammation and oxi-
acid deficiency is prominent throughout the acute dative stress as measured with C-reactive protein
&&
phase. Deficiency was significantly associated with and uric acid concentrations [48 ,49,50], and a
high inflammatory markers, C-reactive protein and reduction in erythropoietin needs [47] in the
ferritin [39]. This condition seems to be a promising chronic population.
candidate for supplementation.

Postoperative pain
Cancer Postoperative pain can be challenging and contrib-
Very high-dose ascorbate is selectively cytotoxic to ute to serious complications, such as the complex
cancer cell lines through the generation of extra- regional pain syndrome and prolonged hospital
cellular H2O2 (Fig. 2). According to an extensive stay. Among the different adjunctive therapies,
review [40], the safety of intravenous ascorbate vitamin C supplementation has also been investi-
has been verified in encouraging pilot clinical stud- gated. A randomized controlled trial shows evidence
ies. The authors conclude that the clinical efficacy of supporting the use of a 2 g preoperative dose of
ascorbate needs to be reassessed using proper dosing vitamin C as an adjunct for reducing postoperative
and route of administration (oral versus intrave- morphine consumption [51]. There is further high-
nous). Ascorbate may enhance the sensitivity to level evidence supporting the fact that perioperative
thermotherapy and reduced toxicity as shown in vitamin C supplementation of 1 g/day for 50 days
ovarian cancer cell lines [41]. Patients submitted to prevents pain after extremity surgery [52,53].

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 Vitamin C in critical care Berger and Oudemans-van Straaten

MONITORING OF PLASMA taken in patients with kidney stones, because high-

CONCENTRATIONS dose vitamin C increases oxalate excretion.
Vitamin C plasma determinations are required for
the diagnosis of deficiency and guidance of supple-
mentation in clinical practice. There are some tech- DOSE RECOMMENDATIONS
nical caveats regarding ascorbic acid determination Knowledge about ascorbic acid in critical care con-
[54]. Unfortunately, this determination requires an ditions is rapidly progressing, but at this stage, the
HPLC setting, and is therefore expensive and not only recommendations concern parenteral nutri-
available for routine clinical care. Several indirect tion; however, even these are minimally supported
methods are available, but the specificity is generally by measured plasma concentrations. The other
poor. In addition, the accurate evaluation of status recommendation must still be considered in the
requires the simultaneous measurement of dehy- research perspectives and have low evidence levels.
droascorbic acid (DHA), the oxidation product of The available literature suggests that the prescribed
ascorbic acid, which is generally not available in dose should depend on the pathology.
clinical settings. Of note, high-dose ascorbic acid
may alter the point-of-care apparatus for blood glu-
cose determinations as shown in a study in major Nutritional supply
burn patients determining glucose [55]. Parenteral nutrition recommendations were revised
Optimal plasma levels and the ‘risk of toxicity’ by American Society of Parenteral and Enteral Nutri-
should be reconsidered. In fact, we do not know at tion in 2009 [56]: 100 mg/day is recommended for
which dose toxicity occurs, though we should be home parenteral nutrition purpose. The require-
very alert for its risk. Considering the results pub- ments for surgical patients on parenteral nutrition
&&
lished by Fowler et al. [17 ], short-term supranormal are still not settled [57,58]. In Japanese patients with
concentrations (Fig. 3) should be studied in research gastrointestinal disorders receiving parenteral nutri-
context for potential antioxidant benefits and pro- tion, with 100 mg/day of ascorbic acid, plasma
oxidant risks. The authors observed a faster recovery concentrations were insufficient [59]. A small
of organ failure. Furthermore, precautions should be randomized trial comparing two ascorbic acid doses
during peripheral parenteral nutrition showed that
500 mg/day, but not 100 mg/day, was adequate for
patients undergoing gastrointestinal surgery [60].
10000
3,000 µM

Intense inflammatory response

Plasma ascorbate (µM)

1000 Intravenous ascorbic acid doses up to 3 g daily for 2–

300 µM 6 days are needed to restore normal plasma concen-
trations [21] or improve the clinical outcomes in
&

100 ICU patients [6 ,35]. Short-term high pharmacologi-

cal doses (up to 16 g ascorbic acid per day in sepsis
15 µM
and 110 g/day in burns) during the acute phase of
overwhelming oxidative stress seem well tolerated
10 &&
and might be beneficial [17 ,36,38]. However, large
randomized studies are warranted to show whether
Placebo Lo-AscA Hi-AscA this really translates into better clinical outcome.
1

0 24 48 72 96
Time (h) Repletion with increased losses
Albeit continuous renal replacement is an estab-
FIGURE 3. Evolution of plasma ascorbic acid levels from lished cause of ascorbic acid depletion along with
admission: the subnormal levels at entry (<50 mmol/l, dotted other micronutrients [44,45], there are no prospec-
line) raised rapidly in the two treatment groups, becoming tive supplementation trials testing plasma concen-
significantly higher than placebo within 12 h (Lo-AscA versus trations or clinical outcomes. Nevertheless, the pro-
placebo P < 0.005, Hi-AscA versus placebo P < 0.0005) oxidative nature of AKI and its treatment, and the
remaining consistently during the study period. The measured losses suggest that at least 500 mg should
intermittent ascorbic acid infusion (every 6 h for 30 min) be delivered daily.
produced sustained steady levels. Reproduced with Patients with enterocutaneous fistulae, particu-
permission from [17 ]. &&
larly high-output fistulas, should be addressed

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Nutrition and the intensive care unit

separately and tightly monitored. Energy require- Financial support and sponsorship
ment may increase up to 1.5 times and require None.
1.5–2.5 g/kg of protein. It is suggested to provide
twice the requirement of vitamins and trace Conflicts of interest
elements, and between 5 and 10 times that of None.
ascorbic acid (>1 g) and zinc [61].
REFERENCES AND RECOMMENDED
Combination with other micronutrients READING
Papers of particular interest, published within the annual period of review, have
Ascorbic acid is part of an antioxidant network, been highlighted as:
& of special interest
providing only one may promote pro-oxidation && of outstanding interest

(Fig. 1). The most frequent combinations are with

1. Dupre-Crochet S, Erard M, Nubetae O. ROS production in phagocytes: why,
a-tocopherol, selenium and zinc. The logical admin- & when, and where? J Leukoc Biol 2013; 94:657–670.
istration of a combination of micronutrients theor- An excellent review illustrating the current limitations for quantitative spatiotem-
poral ROS detection and point out directions for ongoing development.
etically obscures the proper role of each of them and 2. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury:
in this case of vitamin C. But the synergistic inter- present concepts. J Gastroenterol Hepatol 2011; 26 (Suppl. 1):173–
179.
action of a-tocopherol and vitamin C has proven 3. Tullio F, Angotti C, Perrelli MG, et al. Redox balance and cardioprotection.
effective for enhancing the antioxidant capacity of & Basic Res Cardiol 2013; 108:392.
A high-quality review that depicts the mechanisms underlying injury in acute
a-tocopherol [7]. myocardial infarction and how mitochondria are either targets of damage or
The efficiency and real availability of the dose protection from it.
4. May JM, Harrison FE. Role of vitamin C in the function of the vascular
should always be questioned as the stability of the & endothelium. Antioxid Redox Signal 2013; 19:2068–2083.
various vitamins and particularly of ascorbic acid is A very interesting review describing how ascorbic acid can prevent endothelial
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very limited, especially when the various com- basement membrane, stimulating endothelial proliferation, inhibiting apoptosis,
ponents are mixed in one bag for the simplicity of scavenging radical species, and sparing endothelial cell-derived nitric oxide to help
modulate blood flow.
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oxidative-injury-induced microcirculatory impairment and associated organ failure
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sepsis is still unknown, but early supplementation 11. Luo L, Zhang S, Wang Y, et al. Pro-inflammatory role of neutrophil extracellular
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be an important piece of the supportive therapies in sepsis.
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None. ill and injured. J Surg Res 2003; 109:144–148.

200 www.co-clinicalnutrition.com Volume 18  Number 2  March 2015

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 Vitamin C in critical care Berger and Oudemans-van Straaten

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