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Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 +/- 2.4 muM (normal range 50-70 muM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.Trial registration: ClinicalTrials.gov identifier NCT01434121.
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R E S E A R C H Open Access
Phase I safety trial of intravenous ascorbic acid in
patients with severe sepsis
Alpha A Fowler III
1*
, Aamer A Syed
1
, Shelley Knowlson
2
, Robin Sculthorpe
3
, Don Farthing
4
, Christine DeWilde
1
,
Christine A Farthing
4
, Terri L Larus
4
, Erika Martin
5
, Donald F Brophy
5
, Seema Gupta
6
, Medical Respiratory Intensive
Care Unit Nursing
2
, Bernard J Fisher
1
and Ramesh Natarajan
1
Abstract
Background: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in
experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to
determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.
Methods: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive
intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50mg/kg/24h,n=8),orHi-AscA
(200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety
and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored
for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential
Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and
thrombomodulin were monitored.
Results: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9± 2.4 μM (normal range 50-70 μM).
Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were
observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA
scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory
biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused
patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury.
Conclusions: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact
the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.
Trial registration: ClinicalTrials.gov identifier NCT01434121.
Keywords: Ascorbic acid, Biological markers, Clinical trials phase I as topic, Multiple organ failure, Organ dysfunction
scores, Sepsis
Background
The incidence of sepsis and sepsis-associated organ failure
continues to rise in Intensive Care Units worldwide with
studies from multiple countries showing that organ failure
contributes cumulatively to patient mortality [1-3]. Patients
with severe sepsis suffer higher mortality rates compared
to patients with organ failure but no sepsis. Despite over
15,000 patients studied and over 1 billion dollars in study
costs effective sepsis therapy remains elusive [4,5]. Clinical
trials that have targeted mediators of inflammation or
coagulation such as atorvastatin [6] or activated protein
C [7] have not reduced septic mortality, suggesting that
single-target therapy fails to meet the challenges of
complex multicellular activation and interactions.
Recent studies suggest that ascorbic acid may attenuate
pathological responses in septic microvasculature. Armour
et al. and Wu et al. showed that ascorbic acid infusion im-
proved capillary blood flow, microvascular barrier function,
* Correspondence: afowler@mcvh-vcu.edu
1
Division of Pulmonary Disease and Critical Care Medicine, Department of
Internal Medicine, School of Medicine, Virginia Commonwealth University,
PO Box 980050, Richmond, VA 23298-0050, USA
Full list of author information is available at the end of the article
© 2014 Fowler et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication
waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise
stated.
Fowler et al. Journal of Translational Medicine 2014, 12:32
http://www.translational-medicine.com/content/12/1/32
and arteriolar responsiveness to vasoconstrictors in septic
animals [8,9]. Recently, we showed that parenterally infus-
ing ascorbic acid at a concentration of 200 mg/kg attenu-
ated vascular lung injury in septic mice by multiple
mechanisms, including attenuation of the proinflammatory
mediators, enhanced alveolar epithelial barrier function,
increased alveolar fluid clearance, and prevention of sepsis-
induced coagulopathy [10,11]. In addition, ascorbic acid
deficient mice were found to be more susceptible to
sepsis-induced multiple organ dysfunction and parenteral
infusion of ascorbic acid attenuated the injury (lung, kidney,
liver) [12].
Subnormal plasma ascorbic acid concentrations in septic
patients correlate inversely with the incidence of multiple
organ failure and directly with survival [13]. Ascorbic acid
depletion in sepsis results from: 1) ascorbic acid consump-
tion by reduction of plasma free iron, 2) ascorbic acid
consumption by the scavenging of aqueous free radicals,
and 3) by destruction of the oxidized form of ascorbic acid,
dehydroascorbic acid [14]. Dosing and bio-distribution data
in humans show that pharmacological concentrations of
ascorbic acid can only be attained following intravenous
administration [15]. Surprisingly, few studies in critically
ill patients infusing ascorbic acid have been performed.
Nathens and colleagues infused ascorbic acid at 1 gram
every 8 hours combined with oral vitamin E for 28 days in
594 surgically critically ill patients and found a significantly
lower incidence of acute lung injury and multiple organ
failure [16]. Tanaka et al. infused ascorbic acid continuously
at 66 mg/kg/hour for the first 24 hours in patients with
greater than 50% surface area burns and showed signifi-
cantly reduced burn capillary permeability [17]. A single
report (published as abstract only) of a clinical study of
large intravenous doses of ascorbic acid, and other antioxi-
dants (tocopherol, N-acetyl-cysteine, selenium), in patients
with established ARDS showed a 50% reduction in mortal-
ity [18]. Clinical protocols currently in use for hospitalized
septic patients fail to normalize ascorbic acid levels.
Ascorbic acid dosages utilized in this trial arose from our
preclinical work.
In the current trial, we sought to determine whether
intravenous ascorbic acid was safe to administer to critically
ill patients with severe sepsis and to determine if ascorbic
acid had an impact on organ failure and a priori selected
blood biomarkers. We measured C-reactive protein and
procalcitonin as systemic markers of inflammation while
choosing thrombomodulin as a marker of vascular injury
[19-21]. The work reported in this study has previously
been presented at the American Thoracic Society Inter-
national Meeting [22].
Methods
This study was approved by the VCU Institutional Review
Board (IRB). The IRB approval number assigned to this
trial was: HM12903. The trial was conducted under a
randomized double blind placebo-controlled format. A
multi-departmental data safety monitoring board oversaw
the trial.
Patient enrollment
Patients were screened and enrolled following admission
to the Medical Respiratory Intensive Care Unit in the VCU
Medical Center, Richmond, Virginia. Severe sepsis was
defined as: 1) Presence of a systemic inflammatory response:
(fever: >38°C or hypothermia: <36°C (core temp only),
heart rate > 90 beats/min, leukocytosis: >12,000 WBC/μL
or leukopenia: <4,000 WBC/μLor>10%bandforms)[23],
2) Suspected or proven infection,and3)Presence of sepsis-
induced organ dysfunction: Arterial hypoxemia (P
a
O
2
/
F
i
O
2
< 300), systolic blood pressure (SBP) < 90 mm Hg or
SBP decrease > 40 mm Hg unexplained by other causes,
Lactate > 2.5 mMol/L Urine output < 0.5 ml/kg/hour for
greater than two hours despite fluid resuscitation, platelet
count < 100,000, acutely developing coagulopathy (INR >
1.5), Bilirubin > 2 mg/dL. If these three criteria were met
within 48 hours of ICU admission, informed consent was
obtained from family members of patients deemed eligible
for the study. Study groups in this trial were 1) Placebo:5%
dextrose and water; 2) Low dose ascorbic acid (Lo-AscA):
50 mg/kg/24 hours; or 3) High dose ascorbic acid (Hi-
AscA): 200 mg/kg/24 hours. Ascorbic acid dosage was
divided into 4 equal doses and administered over 30 mi-
nutes every 6 hours for 96 hours in 50 ml of 5% dextrose
and water. Study drug infusion was initiated 2 to 4 hours
following informed consent and randomization.
The study blind was established and maintained by the
VCU Investigational Pharmacy Department where the
study drug was prepared, hooded, and dispensed. Subjects
were assigned to one of three dosing groups (0 mg/kg/day,
50 mg/kg/day, or 200 mg/kg/day) in a 1:1:1 ratio using
a randomization scheme generated by using Research
Randomizer [24]. Placebo or study drug was prepared in
50 mL polyvinyl chloride intravenous infusion bags (Viaflex,
Baxter Healthcare, Deerfield, IL). Ascorbic Acid Injection,
USP, (Bioniche Pharma, Lake Forest, IL) was used. Ascorbic
acid or placebo solutions were prepared in matching
volumes with amber shrouding for light protection and to
preserve the blind. Air was removed from IV bags for pro-
tection against ascorbic acid oxidation. Ascorbic acid was
stored at 28°C for up to 24 hours prior to use. Preliminary
experiments showed no oxidation under these brief stor-
age conditions.
Study data management
Collected data was managed using REDCap (Research
Electronic Data Capture), a secure, web-based data collec-
tion and storage tool hosted at VCU [25].
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Assessment of organ failure
Organ failure was assessed using the Sequential Organ
Failure Assessment (SOFA) score described by Vincent
and colleagues [26]. Scores were calculated at enrollment
and at 24, 48, 72, and 96 hours given the predictive value
of serial SOFA scores reported by Ferreira et al. [27].
Laboratory data and physiologic measures for calculating
SOFA scores were monitored daily and recorded into
REDCap. Data was normalized using the delta total SOFA
score (total maximum SOFA score at study entry minus
total maximum SOFA score over the 4-day study period)
[28,29].
Study drug infusion and safety monitoring
Vital signs were monitored every 5 minutes during infusion
and every 5 minutes for 45 minutes afterwards by bedside
Medical Respiratory Intensive Care Unit (MRICU) Nursing
and the investigative team. Patient safety in this Phase I
trial was paramount. Four objective indices were monitored
during and after ascorbic acid infusion: 1) Hypotension: De-
fined as a fall in mean arterial blood pressure of 20 mm Hg
during or following infusion, 2) Tachycardia: Defined as an
increase in heart rate of 20 beats per minute during or fol-
lowing infusion, 3) Hypernatremia: Standard of care utilizes
0.9% saline for volume resuscitation. L-Ascorbic acid prep-
aration used for this study presented a minor sodium load,
therefore a potential for hypernatremia to develop existed
and 4) Nausea or vomiting: were monitored both during
and after ascorbic acid administration by investigators and
by MRICU nursing staff. If one of the adverse events listed
above was observed, ICU nursing was equipped with bed-
side algorithms designed to manage the adverse event. If an
event was observed, drug infusion was halted. If the event
resolved, drug infusion was restarted at 50% of the original
infusion rate. If the event recurred, the patient was removed
from the study. If no adverse event was observed, patients
were infused for 4 days. Patients were then followed clinic-
ally for 28 days.
Blood samples
Whole venous blood was drawn into sterile Vacutainer®
tubes (Becton, Dickinson & Co., Franklin Lakes, NJ): serum
tube (BD 367812, red top, clot activator) and plasma tube
(lavender top, BD 367861, K2EDTA). Serum samples were
allowed to coagulate for 60 min at room temperature.
Plasma and serum were separated by centrifugation. An
aliquot of freshly isolated plasma was processed for ascorbic
acid analysis. Remaining plasma and serum were aliquoted
and frozen at 70°C until assayed.
Plasma ascorbic acid measurement
Plasma Ascorbic Acid Stability: Preliminary work optimized
conditions for stabilizing ascorbic acid in EDTA plasma
samples. Briefly, 0.4 ml of cold 20% trichloroacetic acid
(TCA) and 0.4 ml of cold 0.2% dithiothreitol (DTT)
were added to 0.2 ml of plasma, vortexed for 2 min, and
centrifuged (10,000 g, 10 min, 4°C). Supernatants were
aliquoted and frozen at 70°C for batch analysis. Quality
control samples consisted of normal plasma spiked with
ascorbic acid (100 & 1,000 μM), processed in the same
manner, and stored with patient samples. Plasma Ascorbic
Acid Concentrations: Plasma ascorbic acid levels were
quantified in all patients at enrollment then just prior to
administration of the 12, 24, 36, 48, 72, and 96 hour
ascorbic acid dosing. Concentrations were measured using
high pressure liquid chromatography (HPLC) with UV
detection. Chromatography was performed on an Onyx
MonolithicC18Column(100×4.6mm;Phenomenex,
Torrance, CA) with a mobile phase using a gradient buffer
(dipotassium phosphate), ion pairing reagent (tretrabutyl
amonium chloride), and acetonitrile at a flow rate 0.8 ml/
min. Detection was at 265 nm and ascorbic acid levels
quantified using peak area analysis and external stan-
dardization. Ascorbic acid standards (01,000 μM) were
freshly prepared and treated in the same way as the test
plasma samples.
Biomarkers
Biomarkers measured for this study were identified prior
to the start of the study. C-Reactive Protein (CRP):Ahigh
sensitivity C-reactive protein (hsCRP) assay was performed
in collaboration with Health Diagnostics Laboratories,
Richmond, Virginia using the Roche hsCRP kit (catalog #
11972855216) on a Roche automated chemistry analyzer.
Procalcitonin (PCT): Procalcitonin levels were quantified
using a sandwich ELISA kit according to manufacturers
instructions (RayBiotech, Inc., Norcross, GA). Thrombomo-
dulin (TM): Plasma levels were quantified using an enzyme-
linked immunosorbent assay kit (IMUBIND; American
Diagnostica Inc., Stamford, Connecticut, USA). Samples
were incubated in microwells precoated with a monoclo-
nal antibody specific for human thrombomodulin.
See Additional file 1 for description of methods utilized
for biomarker analysis.
Statistical analysis
All analyses in this study were pre-specified. Statistical
analysis was performed using SAS 9.3 and Graphpad
PRISM 6.0. The results are expressed as means ± SE. Dif-
ferences between and within groups were analyzed using
two-factor analysis of variance with Tukeysstudentized
range test. Summary data is reported as mean ± SEM.
Statistical significance was confirmed at a p value of <0.05.
Organ dysfunction analysis was based on the evolution
(slopes) of the delta daily total SOFA score (change in
daily total SOFA score compared with day 0) over 4
study days by comparing the regression coefficients using
Students t-test [28,29].
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Results
Enrolled study patients
Over a one year period, 35 patients were screened and
26 patients were enrolled. Reasons for excluding the 9
patients are as follows: a) 3 patients had terminal cancer
and were not expected to survive for 24 hours; b) Informed
consent could not be obtained in two homeless septic
patients, and c) family members refused consent in 4
patients. Eight were enrolled in the placebo group, 8
enrolled in the Lo-AscA group, and 10 enrolled in the
Hi-AscA. One patient in the Hi-AscA group was with-
drawn by family members and transferred to another in-
stitution. One other Hi-AscA patient was withdrawn after
Hemophagocytic Syndrome plus sepsis was recognized.
These two patients are not included in the analysis. All
patients received full ICU standard of care support.
Table 1 shows the demographics of enrolled patients. The
APACHE II and SOFA scores between groups were statis-
tically identical. Table 2 indicates the underlying diagnosis
for patients entered into the trial, the organ system affected,
the source and identification of organisms in the patients,
and on day one of entry into the trial whether acute kidney
injury or respiratory failure was present. Secondary out-
comes (i.e., days on vasopressor, Ventilator days, ICU
length of stay and 28 day mortality) are now reported
in Additional file 2: Table S1. The cohort of patients in
this trial had a high incidence of respiratory failure.
Nineteen patients had ARDS at entry as defined by the
Berlin Definition with P
a
O
2
/F
i
O
2
(PF) ratios of less
than 300 and patchy airspace disease on chest imaging.
Five patients had PF ratios above 300. Of the group
with PF ratios above 300 only two were not intubated
for ventilatory support. One patient in the group with PF
ratios above 300 eventually fell below 300 and satisfied the
Berlin Definition of ARDS.
Safety of intravenous ascorbic acid
Safety of ascorbic acid infusion in critically ill patients was a
primary endpoint for this Phase I safety trial. During the
96-hour infusion period, no patients were withdrawn
due to study-related adverse events (i.e., hypotension,
tachycardia, hypernatremia, or nausea/vomiting). Infusions
were halted in one septic patient (Hi-AscA) following in-
fusion #14 (84 hours) for a ventricular arrhythmia later
determined by Cardiology consultants to be electrical
artifact. This patient is included in the analysis.
Plasma ascorbic acid levels
Plasma ascorbic acid levels in all septic patients at enroll-
ment were subnormal (i.e., hyposcorbic) at 17.9 ± 2.4 μM
(normal 50 70 μM) and were not significantly different
at baseline (Figure 1). Ascorbic acid levels in the placebo
group fell from 20.2 (1145) μM at entry to 15.6 (727)
μM on study day 4. Ascorbic acid levels increased 20-fold
in the low dose treatment group from 16.7 (1428) μMat
baseline to 331 (110806) μm on day 4. Ascorbic acid
levels increased dramatically in Hi-AscA patients from
17.0 (1150) μM at baseline to 3,082 (1,592 - 5,722) μm
on day 4. Thus, ascorbic acid levels rose rapidly in the two
treatment groups and were significantly higher than pla-
cebo within twelve hours (Lo-AscA vs. placebo p < 0.005,
Hi-AscA vs. placebo p < 0.0005) remaining consistently
elevated for the 96-hour infusion period. Furthermore,
ascorbic acid levels in the Hi-AscA group were significantly
higher (p < 0.005) than the Lo-AscA group from the 12
hour point forward reaching millimolar concentrations.
These data confirm hyposcorbiclevels present in un-
treated human sepsis and show that intermittent ascorbic
acid infusion every 6 hours produces sustained steady-state
plasma levels.
Impact of ascorbic acid infusion on organ failure
SOFA scores at enrollment were: Placebo 13.3 ± 2.9,
Lo-AscA 10.1 ± 2.0, and Hi-AscA 10.8 ± 4.4 and were
not significantly different across groups. The components
of the SOFA score are listed in Additional file 3: Table S2.
Following normalization of the daily SOFA scores, patients
treated with either dose of ascorbic acid exhibited de-
scending SOFA scores over the 4-day study period (p < 0.05,
slopes significantly non-zero). High dose ascorbic acid
patients exhibited significantly faster declines in the re-
gression slopes of delta daily total SOFA scores over time
compared to placebo (0.043 vs. 0.003, p < 0.01) (Figure 2).
Placebo patients exhibited a gradual rise in SOFA scores.
Though the cohort size is limited, these data suggest that
ascorbic acid infusion significantly attenuates the systemic
organ injury associated with sepsis.
Impact of ascorbic acid infusion on biomarkers
Serum/plasma obtained from enrolled subjects were an-
alyzed for three biomarkers: C-reactive protein (CRP),
procalcitonin (PCT), and thrombomodulin (TM). CRP and
PCT were quantified as surrogates for inflammation while
TM was employed as a surrogate for endothelial injury. At
enrollment, biomarker levels across the three groups were
not significantly different. Serum CRP trended slowly down
over the 96 hour period in the placebo group. Patients
receiving ascorbic acid exhibited rapid reductions in
Table 1 Baseline demographic data of septic patients
treated or not treated with intravenous ascorbic acid
Treatment Gender Age APACHE II
score
a
SOFA
score
b
Placebo 4 male 4 female 54 68 years 20.4 (15 29) 13.3 ± 2.9
Lo-AscA 5 male 3 female 30 70 years 20.4 (12 23) 10.1 ± 2.0
Hi-AscA 4 male 4 female 49 92 years 24.0 (12 33) 10.8 ± 4.4
a
APACHE Acute Physiology and Chronic Health Evaluation, mean (range).
b
SOFA Sequential Organ Failure Assessment, mean ± SE.
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Table 2 Clinical data on patients with severe sepsis
Underlying conditions Source of sepsis Organism Renal failure? Respiratory failure?
Lung cancer Pneumonia Blood: E.coli, Strep bovis no yes
Resp: E.coli
Prodrome with nausea and
vomiting for 7 days
Pneumonia Blood: culture negative no yes
Urine: Legionella antigen positive
ETOH cirrhosis Spontaneous bacterial
peritonitis
Blood: culture negative no yes
Status/Post gastric bypass Urinary tract infection Blood: E. Coli no yes
Obstructive nephrolithiasis
pyelonephritis
Urinary tract infection Blood: E.Coli no yes
Urine: E.Coli
End stage renal disease Catheter sepsis Blood: MRSA yes (prior to admission) yes
Acute myelogenous
leukemia (relapse)
Portacath sepsis Blood: MRSA no yes
Urine: Enterobacter
Influenza Pneumonia with
coexistent Influenza A
Blood: Strep pneumonia no yes
Resp: Influenza A
Diabetes mellitus Infected diabetic foot
ulcer
Blood: Staph aureus no yes
Chronic kidney disease Body Fluid: Staph aureus
Gout Resp: MRSA
Head and neck cancer Pneumonia Blood: culture negative no yes
Resp: culture negative
Diabetes mellitus Pneumonia and colitis Blood: culture negative yes (dialysis required) yes
Congestive heart failure
Gastrointestinal hemorrhage Resp: MRSA
Cellulitis Pneumonia Blood: Group a strep. no no
Hypercholesterolemia Urinary tract infection
Multiple myeloma PneumoniaUrinary tract
infection
Blood: Gram positive cocci no yes
Urine: Proteus mirabilis
Non-Hodgkins lymphoma Pancreatitis Resp: Aspergillus fumigatus no yes
Bone marrow transplant Intra-abdominal sepsis Blood: Gram negative rods,
Gram positive cocci
no yes
Bowel perforation
Post allogeneic bone marrow
transplant
Pneumonia Blood: culture negative no yes
Chronic opiate use Aspiration pneumonia Blood: Strep. pneumonia no yes
Found obtunded Resp: Strep. pneumonia,
Candida glabrata
Diabetes mellitus Aspiration pneumonia Resp: Gram negative rods,
gram positive cocci
yes (prior to admission) yes
End stage renal disease
Chronic obstructive pulmonary
disease
Pneumonia Blood: culture negative no yes
Resp: Acinetobacter,
Stenotrophomonas maltiphilia
Toxic epidermal necrolysis Skin Blood: MRSA yes yes
Acute renal failure
Alcoholic cirrhosis Subacute bacterial
peritonitis
Blood: culture negative no no
Hepatorenal syndrome
Chronic obstructive pulmonary
disease
Pneumonia Blood: Gram positive rods no yes
Severe ankylosing spondylitis Urinary tract infection Blood: Klebsiella pneumonia no yes
Fowler et al. Journal of Translational Medicine 2014, 12:32 Page 5 of 10
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CRP levels achieving significantly lower levels when
compared to their own baseline and placebo by 24 hours
(Figure 3A, p < 0.05). PCT levels trended higher in placebo-
infused patients 24 hours following the onset of sepsis
though not reaching statistical significance. Serum PCT
levels in patients receiving high dose ascorbic acid declined,
becoming significantly lower than baseline by 48 hours
(Figure 3B, p < 0.05). PCT in patients receiving high dose
ascorbic acid continued to decline over the 96-hour period.
Plasma TM levels in patients randomized to placebo were
not different from the ascorbic acid groups at baseline.
Placebo patients began to trend upwards beyond 36 hours,
remaining elevated when compared to ascorbic acid treated
patients though the values were not statistically significant
(Figure 4). Importantly ascorbic acid treated patients did
not exhibit the upward trend in TM levels observed in
placebo-infused patients. These results suggest that as-
corbic acid infusion produces early reductions in pro-
inflammatory mediators in patients with severe sepsis.
The results further suggest that ascorbic acid infusion
attenuates the evolution of endothelial injury characteris-
tic of severe sepsis in humans.
Discussion
This phase I trial focused on the safety of administering
intravenous ascorbic acid to patients with severe sepsis.
The intravenous route of administration was chosen in
this trial in order to achieve high ascorbic acid plasma
levels. Padayatty and colleagues showed that high-level
ascorbic acid plasma concentrations could only be achieved
by intravenous administration [15]. Prior human studies
employing pharmacologic ascorbic acid dosing report no
adverse events. Nathens et al. administered 1 gram of as-
corbic acid every 8 hours for 28 days to surgically critically
ill patients with no ill effects [16]. Tanaka et al. adminis-
tered 66 mg/kg/hour for 24 hours to patients with 50%
Table 2 Clinical data on patients with severe sepsis (Continued)
Urine: Klebsiella pneumoniaSevere aortic stenosis
Hepatitis C cirrhosis Health care acquired
pneumonia
Blood: culture negative yes (dialysis required) yes
Urine: EnterococcusEsophageal varicies
Systemic mastocytosis Pneumonia Blood: culture negative no yes
Congestive heart failure Resp: Budding yeast with
pseudohyphae
Figure 1 Plasma ascorbic acid levels following intravenous
infusion of ascorbic acid. Plasma ascorbic acid levels were
subnormal at entry (<50 μM, dotted line). Ascorbic acid levels rose
rapidly in the two treatment groups and were significantly higher
than placebo within twelve hours (Lo-AscA vs. placebo p < 0.005,
Hi-AscA vs. placebo p < 0.0005) remaining consistently elevated for
96 hours. Ascorbic acid levels in the Hi-AscA group were significantly
higher than the Lo-AscA group from the 12 hour point forward.
These data show that an intermittent ascorbic acid infusion protocol
(every 6 hours) produces sustained steady state levels in patients
with severe sepsis. Placebo (О), Lo-AscA (), Hi-AscA ().
Figure 2 Effect of ascorbic acid infusion on Sequential Organ
Failure Assessment (SOFA) score (days 04). Daily mean SOFA
scores decreased over time with both doses of ascorbic acid infusion
(p <0.05 significantly non-zero) with the higher dose significantly less
than placebo (Hi-AscA vs. placebo p<0.01). Placebo (О), Lo-AscA (),
Hi-AscA ().
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surface area burns with no adverse events [17]. Hoffer
et al. intravenously administered up to 90 grams of ascorbic
acid 3 times weekly to patients with advanced malignancy
with no adverse events [30]. The dosing protocols we
chose for this trial arose out of our preclinical work.
No patient in the low or high dose ascorbic acid treat-
ment arms of this study suffered any identifiable adverse
event. As noted above, the one instance in which ascorbic
acid infusion was halted for a cardiac rhythm disturbance
was determined to be artifact by the Division of Cardiology.
Thus, a pharmacologic ascorbic acid treatment strategy in
critically ill patients with severe sepsis appears to be safe.
Prior studies show that patients with severe sepsis exhibit
significantly reduced plasma ascorbic acid levels upon
admission to intensive care [31]. The mean initial plasma
ascorbic acid level for all septic patients in this study was
17.9 ± 2.4 μM compared to normal human plasma levels
of 50 70 μM (Figure 1). Prior studies [13,14,26], and the
current study show that subnormal plasma ascorbic acid
levels are a predictable feature in patients with severe
sepsis. Importantly, Placebo patients exhibited no change
in plasma ascorbic acid levels throughout the 4-day study
period despite receiving full ICU standard of care practice
for severe sepsis (Figure 1). Ascorbic acid depletion in
sepsis results from ascorbic acid consumption by the
reduction of plasma free iron, ascorbic acid consumption
by the scavenging of aqueous free radicals (peroxyl rad-
icals), and by the destruction of the oxidized form of
ascorbic acid dehydroascorbic acid [14]. Sepsis further
inhibits intracellular reduction of dehydroascorbic acid,
producing acute intracellular ascorbic acid depletion.
Sepsis-induced ascorbic aciddestructionpermitsun-
controlled oxidant activity which amplifies tissue injury
[14,32,33]. Ascorbic acid treated patients in this study ex-
hibited rapid and sustained increases in plasma ascorbic
acid levels using an intermittent every six hours adminis-
tration protocol (Figure 1).
SOFA scores are robust indicators of mortality during
critical illness. SOFA score increases during the first 48
hours of ICU care predict a mortality rate of at least 50%
[26]. In this study, the extent of organ failure accompanying
patients with severe sepsis was high with an average SOFA
score for all patients equal to 11.4 ± 3 confirming that
multiple organ failure was present at enrollment. Given
that the mean plasma ascorbic acid levels on admission
were subnormal (17.9 ± 2.4 μM), a mean initial SOFA
score of 11.4 ± 3 in patients with severe sepsis was not
Figure 3 Serum C-reactive protein (CRP) and procalcitonin
levels in septic placebo controls and ascorbic acid infused patients.
(A) Both the Lo-AscA and the Hi-AscA dosages produced rapid
reductions in serum CRP levels, becoming significantly lower than
placebo (*p < 0.05 vs placebo) as early as 24 hours. Ascorbic acid
infusion reduced CRP levels in both groups throughout the 4
studydays(#p<0.05vs0hr).CRPlevelsinplacebopatients
slowlyfelloverthecourseofthe4daystudyperiod.(B) Patients
in the Lo-AscA and Hi-AscA groups exhibited reduced serum PCT
levels beginning at 12 hours. Patients in the Hi-VitC group exhibited
further significant reduction in serum PCT between 36 to 48 hours
(#p < 0.05 vs 0 hr). Placebo patients exhibited a trend towards increased
PCT levels which declined starting at 72 hours post onset of sepsis.
Placebo (О), Lo-AscA (), Hi-AscA ().
Figure 4 Plasma thrombomodulin (TM) levels measured in
septic placebo controls and ascorbic acid infused patients.
Plasma TM levels measured in the ascorbic acid infused patients
exhibited no rise throughout the 4 days of study. Patients in the
placebo group showed a trend towards increased plasma TM levels
beginning at 36 hours, though it did not achieve statistical
significance. Placebo (О), Lo-AscA (), Hi-AscA ().
Fowler et al. Journal of Translational Medicine 2014, 12:32 Page 7 of 10
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surprising. This study is in agreement with other studies
which show that plasma ascorbic acid levels in severe
sepsis correlate inversely with the incidence of multiple
organ failure [13]. We showed that the addition of ascorbic
acid to standard of care practice (i.e., fluid resuscitation,
antibiotics, vasopressor medication) for patients with
severe sepsis significantly reduced organ injury. Ascorbic
acid treated patients exhibited prompt and sustained
reductions in SOFA scores during the 4-day treatment
regimen unlike placebo controls where SOFA scores slowly
increased over time. SOFA score reduction was most re-
markable in patients receiving the high dose ascorbic acid
infusion (Figure 2).
C-reactive protein (CRP) [19] and procalcitonin (PCT)
[20] levels are known to correlate with the overall extent
of infection and higher levels of both have both been
linked to higher incidences of organ injury and death in
the critically ill. CRP in circulation has a short half-life
of approximately 19 hours. Thus, the kinetics of CRP
make it a useful monitor for tracking the inflammatory
response produced by infection, and the response to
antibiotic treatment. Lobo et al. reported that patients
with CRP levels greater than 10 mg/dL at ICU admission
exhibited significantly higher rates of multiple organ fail-
ure as well as higher mortality rates [34]. A decrease in
CRP levels in Lobos study after 48 hours was associated
with a mortality rate of only 15.4%, while a persistently
high CRP level was associated with a mortality rate of
60.9%. Both low and high dose ascorbic acid infusion in
this trial promptly reduced serum CRP levels in septic
patients (Figure 3A). Thus, the findings in this study
support the findings of Lobo et al. with descending CRP
levels being associated with lower mortality rate and re-
duced levels or organ failure. Jensen and colleagues found
that high maximal procalcitonin levels were an early inde-
pendent predictor of all-cause mortality in a 90-day follow-
up period after intensive care unit admission [20]. Karlsson
and colleagues [21] showed that mortality in patients with
severe sepsis was lower in those patients in whom procalci-
tonin concentrations fell by more than 50% at 72 hours
with respect to initial values. Infusion of ascorbic acid into
patients with severe sepsis in this study reduced serum
procalcitonin levels by greater than 50% (Figure 3B).
Thrombomodulin is an endothelial cell bound molecule
that captures thrombin holding it adjacent to protein C
bound to its receptor (endothelial protein C receptor).
Elevated soluble TM in the circulation indicates endothelial
cell injury [35]. Lin et al. reported that increased TM levels
correlated with the extent of organ failure and mortality in
patients with sepsis [36]. In the current study, thrombo-
modulin levels in patients randomized to placebo began
to rise at approximately 36 hours into the study period,
indicating sepsis-induced endothelial injury (Figure 4).
Patients randomized to receive either dose of ascorbic acid
exhibited no subsequent rise in plasma thrombomodulin.
Though our patient numbers were small, these early results
suggestthatintravenousascorbic acid acts to attenuate the
proinflammatory state of sepsis and perhaps attenuates the
development of endothelial injury.
On the basis of this study and our prior preclinical
studies, we speculate as to the pleiotropic mechanisms by
which ascorbic acid would be beneficial in sepsis. Ascorbic
acid is rapidly taken up by endothelial cells in millimolar
quantities where it scavenges reactive oxygen species and
increases endothelial nitric oxide synthase-derived nitric
oxide by restoring tetrahydrobiopterin content, thus, in-
creasing bioavailable nitric oxide. As we and others have
shown in basic investigations [10,11,37], by inhibiting
NFκB activation, ascorbic acid could potentially attenu-
ate the cytokine stormthat arises due to NFκBdriven
genes known to be activated in sepsis. Septic ascorbic
acid-deficient neutrophils fail to undergo normal apop-
tosis. Rather, they undergo necrosis thereby releasing
hydrolytic enzymes in tissue beds, thus contributing to
organ injury. We speculate that intravenous ascorbic
acid acts to restore neutrophil ascorbic acid levels. Re-
pletion of ascorbic acid in this way allows for normal
apoptosis, thus, preventing the release of organ dam-
aging hydrolytic enzymes. A multitude of biological
mechanisms are active in patients with sepsis and they
promote multiple organ injury and death.
Tens of thousands of lives are lost across the world an-
nually due to severe sepsis [1,38-40]. Multiple treatment
trials have failed to measurably improve outcomes. The
majority of trials have singly eliminated certain proinflam-
matory mediators which research has suggested promotes
tissue damage. The single mediator approach has largely
been unsuccessful. The results from this small phase I
safety trial suggest that administering ascorbic acid in
pharmacological dosages to critically ill patients with
sepsis is safe and that it may provide adjunctive therapy
in the treatment of severe sepsis. A larger phase II proof-
of-concept trial is needed.
Conclusions
This phase I trial shows that aggressive repletion of plasma
ascorbic acid levels in patients with severe sepsis is safe.
This early work in septic patients suggests that pharmaco-
logic ascorbic acid repletion reduces the extent of multiple
organ failure and attenuates circulating injury biomarker
levels.
Additional files
Additional file 1: Patient Flow Diagram. Flow diagram of the progress
through the phases of the safety trial (enrollment, allocation, follow-up,
and analysis).
Fowler et al. Journal of Translational Medicine 2014, 12:32 Page 8 of 10
http://www.translational-medicine.com/content/12/1/32
Additional file 2: Table S1. Secondary outcomes of septic patients
treated or not treated with intravenous ascorbic acid. Includes days on
vasopressor, ventilator free days, ICU length of stay, and 28-day mortality.
Additional file 3: Table S2: Components of the Sequential Organ Failure
Assessment (SOFA) scoring system. Describes the clinical parameters of the
scoring system.
Abbreviations
AscA: Ascorbic acid; CRP: C-reactive protein; PCT: Procalcitonin;
SOFA: Sequential organ failure assessment; TM: Thrombomodulin.
Competing interests
The authors declare that they have no competing interests.
Authorscontributions
AAF, RN, BJF, AAS: Hypothesis/delineation. AAF, AAS, DF, RS, SK, CD: Study
design. AAF, AAS, RN, BJF, DF, CAF, TLL, CD, SG, EM, DFB, MRICU Nursing:
Acquisition of data/analysis. AAF, RN, BJF, DF, RS: Interpretation of data/
writing the article. AAF, RN, AAS, and BJF conceived, designed, or planned
the study, interpreted the results, and wrote sections of the initial draft. DF,
CAF, and TLL designed, validated and performed the plasma ascorbic acid
HPLC analysis. SK, CD aided in study design and data collection. RS helped
design the study and wrote sections of the initial draft. SG supervised
biomarker analysis and interpretation of results. EM and DFB provided
substantial review and suggestions of the initial draft. All authors read and
approved the final manuscript.
Acknowledgement
The authors wish to acknowledge support for this phase I trial from: 1) The
Aubrey Sage Macfarlane Acute Lung Injury Fund, 2) VCU Clinical and
Translational Science Award UL1TR000058 from the National Center for
Advancing Translational Sciences, 3) VCU Investigational Pharmacy Services,
4) The Jeffress Memorial Trust, and 5) The AD Williams Trust.
Author details
1
Division of Pulmonary Disease and Critical Care Medicine, Department of
Internal Medicine, School of Medicine, Virginia Commonwealth University,
PO Box 980050, Richmond, VA 23298-0050, USA.
2
Department of Critical Care
Nursing, Virginia Commonwealth University Health System, Richmond,
Virginia, USA.
3
Investigational Drug Services, Department of Pharmacy
Services, School of Pharmacy, Virginia Commonwealth University, Richmond,
Virginia, USA.
4
Division of Nephrology, Department of Internal Medicine,
School of Medicine, Virginia Commonwealth University, Richmond, Virginia,
USA.
5
Department of Pharmacotherapy & Outcomes Science, School of
Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.
6
Health Diagnostic Laboratory, Richmond, Virginia, USA.
Received: 12 November 2013 Accepted: 2 January 2014
Published: 31 January 2014
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doi:10.1186/1479-5876-12-32
Cite this article as: Fowler et al.:Phase I safety trial of intravenous
ascorbic acid in patients with severe sepsis. Journal of Translational
Medicine 2014 12:32.
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... It can also regulate the immune system, maintain circulating cytokine homeostasis, and exhibit anti-infammatory and antioxidant properties [7]. Te level of vitamin C is often lower in patients with sepsis [8,9]; therefore, vitamin C supplementation has become one of the measures to treat sepsis. Clinical studies of vitamin C in the treatment of sepsis have shown mixed results on the mortality of patients. ...
... Subsequently, we removed other 32 studies, including two with no full-text or abstract, fve with no outcome measures, two systematic reviews, six reviews, six study protocols, and eleven retrospective studies. Finally, 24 eligible pieces of literature were included in the metaanalysis, with a total of 3,759 patients enrolled in the study [8,[10][11][12][13][14][15][16][17][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Te selection fow diagram is presented in Figure 1. ...
... Te characteristics of the 24 studies, including 23 full-text [8, 10-17, 23-35, 37] and 1 abstract [36], are shown in Table 1. Of those, ten studies were conducted in Asia [11,12,17,23,25,30,31,[35][36][37], nine in North America [8,10,13,14,16,28,29,32,33], three in Africa [24,27,34], and only one in Oceania. Te study populations were mainly enriched in Asia and North America. ...
Article
Full-text available
Sepsis is a high-incidence disease and demands intensive care. Finding effective treatment is the key to cure sepsis. Studies have shown a lower level of vitamin C in patients with sepsis. Therefore, vitamin C supplementation has become one of the measures to treat sepsis. However, the clinical studies of vitamin C in the treatment of sepsis have been controversial. We performed a meta-analysis to evaluate vitamin C’s efficacy and safety in the treatment of sepsis. We searched four electronic databases: PubMed, Embase, Web of Science, and the Cochrane Library, and two researchers independently screened 24 eligible RCTs published in English. Our review demonstrates that intravenous (IV) vitamin C might improve short-term mortality (RR, 0.82; 95% CI, 0.65–1.02; P = 0.07 ; and I2 = 45%) and overall mortality (RR, 0.86; 95% CI, 0.74–1.01; P = 0.06 ; and I2 = 51%) of patients with sepsis. Moreover, the SOFA score of patients with sepsis improved significantly after treatment with vitamin C for over 72 hours (RR, 0.26; 95% CI, 0.09–0.42; P = 0.002 ; and I2 = 0%). The main results of our study were moderate-quality evidence. More high-quality, multicenter RCTs are needed to provide more substantial evidence on the efficacy and safety of IV vitamin C for sepsis.
... g of vitamin C per day is sufficient in the normal condition [23,46]. With HDIVC (approximately 12 g per day for 4 days), vitamin C levels are elevated 20 to 500 folds from the physiologic level with the benefit of reduced organ failure and 28-day mortality, without the significant side effects, partly due to the short course of the administration [47,48]. However, the concerns about hyperoxaluria and calcium-oxalate stone, especially in patients with a renal impairment which is common in patients with sepsis, and the possible enhanced oxidative stress are raised with HDIVC [49]. ...
... Furthermore, vitamin C also activates nuclear factor-kappa B (NF-κB) which leads to an increase in PAD4 expression and facilitates the transportation of MPO and NE from the cytosol into the nucleus causing an enhancement in NETs formation [81]. Hence, the low concentration of vitamin C might act as an anti-oxidant through the negative-charged-anion ascorbate that inhibits NETosis [47], while the high vitamin C concentrations might facilitate NETosis via ROS induction [79]. Neutrophils in mice with vitamin C deficiency also demonstrate the upregulated signaling of autophagy (the reuse of the damaged cell parts by conserved degradation of the cell that unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism) compared with the healthy mice [47,87]. ...
... Hence, the low concentration of vitamin C might act as an anti-oxidant through the negative-charged-anion ascorbate that inhibits NETosis [47], while the high vitamin C concentrations might facilitate NETosis via ROS induction [79]. Neutrophils in mice with vitamin C deficiency also demonstrate the upregulated signaling of autophagy (the reuse of the damaged cell parts by conserved degradation of the cell that unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism) compared with the healthy mice [47,87]. However, impacts of the high vitamin C concentrations on other non-NETs processes of cell death (apoptosis and autophagy) of neutrophils during sepsis are still unknown. ...
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Vitamin C (ascorbic acid), a water-soluble essential vitamin, is well-known as an antioxidant and an essential substrate for several neutrophil functions. Because of (i) the importance of neutrophils in microbial control and (ii) the relatively low vitamin C level in neutrophils and in plasma during stress, vitamin C has been studied in sepsis (a life-threatening organ dysfunction from severe infection). Surprisingly, the supraphysiologic blood level of vitamin C (higher than 5 mM) after the high-dose intravenous vitamin C (HDIVC) for 4 days possibly induces the pro-oxidant effect in the extracellular space. As such, HDIVC demonstrates beneficial effects in sepsis which might be due to the impacts on an enhanced microbicidal activity through the improved activity indirectly via enhanced neutrophil functions and directly from the extracellular pro-oxidant effect on the organismal membrane. The concentration-related vitamin C properties are also observed in the neutrophil extracellular traps (NETs) formation as ascorbate inhibits NETs at 1 mM (or less) but facilitates NETs at 5 mM (or higher) concentration. The longer duration of HDIVC administration might be harmful in sepsis because NETs and pro-oxidants are partly responsible for sepsis-induced injuries, despite the possible microbicidal benefit. Despite the negative results in several randomized control trials, the short course HDIVC might be interesting to use in some selected groups, such as against anti-biotic resistant organisms. More studies on the proper use of vitamin C, a low-cost and widely available drug, in sepsis are warranted.
... In critically ill septic patients, plasma vitamin C levels greatly decrease and facilitate ROS and RNS generation [48], which is consistent with findings that correlate low vitamin C levels to a higher incidence of organic failure and worse outcomes on septic patients [49]. ...
... In this paper we specifically focused on vitamin C, vitamin E, NAC, and selenium. Vitamin C and Vitamin E are ROS scavenger molecules [48,62]. Vitamin C can act both on the directly by scavenging ROS and indirectly abrogating ROS production. ...
... Vitamin C can act both on the directly by scavenging ROS and indirectly abrogating ROS production. In turn, vitamin E can regulate mitochondrial ROS overproduction and both vitamins can contribute to counteract the development of endothelial dysfunction [48,62]. The role of selenium is related to the modulation of the activity of antioxidant enzymes, since it participates in the synthesis of GSH-Px [52], whose action is further enhanced by NAC as donor of GSH [61], also leading to a reduction of the endothelial dysfunction. ...
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Septic shock currently represents one of the main causes of mortality in critical patient units with an increase in its incidence in recent years, and it is also associated with a high burden of morbidity in surviving patients. Within the pathogenesis of sepsis, oxidative stress plays an important role. The excessive formation of reactive oxygen species (ROS) leads to mitochondrial damage and vasomotor dysfunction that characterizes those patients who fall into septic shock. Currently, despite numerous studies carried out in patients with septic shock of different causes, effective therapies have not yet been developed to reduce the morbidity and mortality associated with this pathology. Despite the contribution of ROS in the pathophysiology of sepsis and septic shock, most studies performed in humans, with antioxidant monotherapies, have not resulted in promising data. Nevertheless, some interventions with compounds such as ascorbate, N-acetylcysteine, and selenium would have a positive effect in reducing the morbidity and mortality associated with this pathology. However, more studies are required to demonstrate the efficacy of these therapies. Taking into account the multifactorial features of the pathophysiology of sepsis, we put forward the hypothesis that a supplementation based on the association of more than one antioxidant compound should result in a synergistic or additive effect, thus improving the beneficial effects of each of them alone, potentially serving as a pharmacological adjunct resource to standard therapy to reduce sepsis complications. Therefore, in this review, it is proposed that the use of combined antioxidant therapies could lead to a better clinical outcome of patients with sepsis or septic shock, given the relevance of oxidative stress in the pathogenesis of this multi-organ dysfunction.
... Mögliche Nachteile einer Vitamin-C-Gabe [13] sowie eine Reduktion der Mortalität bei ARDS-PatientInnen ("CITRIS-ALI"-Studie; [14]) in den jeweiligen Vitamin-C-Gruppen zeigte. Zudem gibt es verschiedene systematische Übersichtsarbeiten, die -erneut exemplarisch für vielebei herzchirurgischen [7] oder allgemein intensivmedizinischen PatientInnen [15] teilweise deutliche klinische Vorteile einer Vitamin-C-Monotherapie nachwiesen. ...
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Micronutrient supplementation as part of the medical nutrition therapy for critically ill patients has received much attention in the past few years. Nevertheless, in clinical practice uncertainty remains about the optimal supplementation strategy, including which substance at which dosage should be administered at what time to specific groups of patients. Thus, the aim of this narrative review is to summarize the current evidence and recommendations for the micronutrients vitamin C and vitamin D. The physiological and pathophysiological roles of both vitamins are presented, recently published clinical trials are discussed, and the recommendations of the current guidelines are summarized. In addition, pragmatic tips for use in everyday clinical practice in the intensive care unit are given.
... Rationale A meta-analysis was performed using 11 RCTs [608,[675][676][677][678][679][680][681][682][683][684]. The estimated values of the desirable anticipated effects were as follows: 28-day mortality yielded a RD of 55 fewer per 1000 (95%CI: 131 fewer to 52 more) (5 RCTs, n = 1646), in-hospital mortality yielded an RD of 25 fewer per 1000 (95%CI: 105 fewer to 83 more) (7 RCTs, n = 1798), the length of stay in the ICU yielded a MD of 0.58 days shorter (95%CI: 1.45 shorter to 0.28 longer) (6 RCTs, n = 1394), and AKI yielded an RD of 18 fewer per 1000 (95%CI: 111 fewer to 92 more) (2 RCTs, n = 248). ...
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The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.
... Due to increased metabolism, critically ill patients with septic shock have hypovitaminosis C despite receiving standard parenteral nutrition [9]. Rapid correction of hypovitaminosis C through intravenous administration has been found to decrease the risk of organ failure and lower pro-inflammatory markers in septic patients [10]. Prior studies showed that supraphysiologic doses of vitamin C are required for correction among septic and critically ill patients [9,11]. ...
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Sepsis is a substantial healthcare burden, and its management continues to be a major challenge. Prior studies demonstrate conflicting evidence regarding the utility of vitamin C in sepsis. This systematic review and meta-analysis aim to collect data among critically ill patients (sepsis/septic shock), comparing the efficacy of parenteral vitamin C with standard care. A literature review was conducted using databases including PubMed, Web of Science, Google Scholar, and the Cochrane Library to identify randomized controlled trials (RCTs) and observational studies comparing intravenous vitamin C alone or in combination with thiamine or glucocorticoids to the standard of care. We identified 11 RCTs and seven retrospective cohort studies. The primary outcome was 28-day mortality. Secondary outcomes included intensive care unit (ICU) length of stay, change in Sequential Organ Failure Assessment (SOFA) score, duration of vasopressor use, and duration of mechanical ventilation. A total of 18 studies with 4078 patients were included in our final analysis. Overall, we found no mortality reduction in patients treated with vitamin C compared to standard of care (odds ratio (OR) 0.92; 95% confidence interval (CI) 0.78 to 1.09; p = 0.34). Studies that reported a change in SOFA scores, ICU length of stay, duration of mechanical ventilation, or duration of vasopressor use did not show any significant difference between groups. Subgroup analysis with RCT versus observational studies and vitamin C dosage regimens did not show any difference. Among patients with sepsis or septic shock, treatment with vitamin C was not associated with a reduction in mortality, ICU length of stay, change in SOFA score, duration of vasopressor use, or duration of mechanical ventilation. Further studies are needed to demonstrate the potential role of vitamin C in the management of sepsis.
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Many critically ill patients are vitamin D and vitamin C deficient and the current international guidelines state that hypovitaminoses should be compensated. However, uncertainty about optimal dosage, timing and indication exists in clinical routine, mainly due to the conflicting evidence. This narrative review discusses both micronutrients with regards to pathophysiology, clinical evidence of benefits, potential risks, and guideline recommendations. Evidence generated from the most recent clinical trials are summarized and discussed. In addition, pragmatic tips for the application of these vitamins in the clinical routine are given. The supplementations of vitamin D and C represent cost-effective and simple interventions with excellent safety profiles. Regarding vitamin D, critically ill individuals require a loading dose to improve 25(OH)D levels within a few days, followed by a daily or weekly maintenance dose, usually higher doses than healthy individuals are needed. For vitamin C, dosages of 100–200 mg/d are recommended for patients receiving parenteral nutrition, but needs may be as high as 2–3 g/d in acutely ill patients.
Chapter
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Objective: Based on previous studies in the sepsis population, Vitamin C could prevent injuries when administered in high doses and before the damage is established. This study aimed to evaluate the protective potentials of high-dose Vitamin C in the progression of coronavirus disease 2019 (COVID-19). Methods: A double-blind, placebo-controlled clinical trial was conducted. Patients with moderate-to-severe disease severity based on the World Health Organization definition were enrolled and received 12 g/d Vitamin C (high-dose intravenous Vitamin C [HDIVC]) or placebo for 4 days. Sequential Organ Failure Assessment (SOFA) score as a primary outcome, National Early Warning Score, Ordinal Scale of Clinical Improvement, and cytokine storm biomarkers were recorded on days 0, 3, and 5. Survival was also assessed on day 28 after enrollment. Findings: Seventy-four patients (37 patients in each group) were enrolled from April 5, 2020, to November 19, 2020, and all patients completed follow-up. A lower increase in SOFA score during the first 3 days of treatment (+0.026 vs. +0.204) and a higher decrease in this parameter in the last 2 days (−0.462 vs. −0.036) were observed in the treatment group. However, these differences did not reach a significance level (P = 0.57 and 0.12, respectively). Other indices of clinical and biological improvement, length of hospitalization, and intensive care unit admission days were the same between the two groups. Treatment did not affect the 28-day mortality. Conclusion: Among patients with moderate-to-severe disease of COVID-19, the use of HDIVC plus standard care resulted in no significant difference in SOFA score or 28-day mortality compared to the standard care alone.
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Background: Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown. Materials and methods: Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells. Results: FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice. Conclusions: VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.
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Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage. Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions. We measured baseline total vitamin C and bleomycin-detectable “free” iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects. Vitamin C concentrations were decreased in patients compared to healthy subjects (p<0.0001), and “free” iron was increased (p < 0.002). Preinfusion ascorbyl radical concentrations were not different in patients and controls. Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls. In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging. This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised “free” iron levels.
Article
Hypothesis High-dose ascorbic acid (vitamin C) therapy (66 mg/kg per hour) attenuates postburn lipid peroxidation, resuscitation fluid volume requirements, and edema generation in severely burned patients.Study Design and Setting A prospective, randomized study at a university trauma and critical care center in Japan.Subjects and Methods Thirty-seven patients with burns over more than 30% of their total body surface area (TBSA) hospitalized within 2 hours after injury were randomly divided into ascorbic acid and control groups. Fluid resuscitation was performed using Ringer lactate solution to maintain stable hemodynamic measurements and adequate urine output (0.5-1.0 mL/kg per hour). In the ascorbic acid group (n=19; mean burn size, 63% ± 26% TBSA; mean burn index, 57 ± 26; inhalation injury, 15/19), ascorbic acid was infused during the initial 24-hour study period. In the control group (n=18; mean burn size, 53% ± 17% TBSA; mean burn index, 47 ± 13; inhalation injury, 12/18), no ascorbic acid was infused. We compared hemodynamic and respiratory measurements, lipid peroxidation, and fluid balance for 96 hours after injury. Two-way analysis of variance and Tukey test were used to analyze the data.Results Heart rate, mean arterial pressure, central venous pressure, arterial pH, base deficit, and urine outputs were equivalent in both groups. The 24-hour total fluid infusion volumes in the control and ascorbic acid groups were 5.5 ± 3.1 and 3.0 ± 1.7 mL/kg per percentage of burn area, respectively (P<.01). In the first 24 hours, the ascorbic acid group gained 9.2% ± 8.2% of pretreatment weight; controls, 17.8% ± 6.9%. Burned tissue water content was 6.1 ± 1.8 vs 2.6 ± 1.7 mL/g of dry weight in the control and ascorbic acid groups, respectively (P<.01). Fluid retention in the second 24 hours was also significantly reduced in the ascorbic acid group. In the control group, the ratio of PaO2 to fraction of inspired oxygen at 18, 24, 36, 48, and 72 hours after injury was less than that of the ascorbic acid group (P<.01). The length of mechanical ventilation in the control and ascorbic acid groups was 21.3 ± 15.6 and 12.1 ± 8.8 days, respectively (P<.05). Serum malondialdehyde levels were lower in the ascorbic acid group at 18, 24, and 36 hours after injury (P<.05).Conclusions Adjuvant administration of high-dose ascorbic acid during the first 24 hours after thermal injury significantly reduces resuscitation fluid volume requirements, body weight gain, and wound edema. A reduction in the severity of respiratory dysfunction was also apparent in these patients.
Article
Context Evaluation of trends in organ dysfunction in critically ill patients may help predict outcome.Objective To determine the usefulness of repeated measurement the Sequential Organ Failure Assessment (SOFA) score for prediction of mortality in intensive care unit (ICU) patients.Design Prospective, observational cohort study conducted from April 1 to July 31, 1999.Setting A 31-bed medicosurgical ICU at a university hospital in Belgium.Patients Three hundred fifty-two consecutive patients (mean age, 59 years) admitted to the ICU for more than 24 hours for whom the SOFA score was calculated on admission and every 48 hours until discharge.Main Outcome Measures Initial SOFA score (0-24), Δ-SOFA scores (differences between subsequent scores), and the highest and mean SOFA scores obtained during the ICU stay and their correlations with mortality.Results The initial, highest, and mean SOFA scores correlated well with mortality. Initial and highest scores of more than 11 or mean scores of more than 5 corresponded to mortality of more than 80%. The predictive value of the mean score was independent of the length of ICU stay. In univariate analysis, mean and highest SOFA scores had the strongest correlation with mortality, followed by Δ-SOFA and initial SOFA scores. The area under the receiver operating characteristic curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score during the first 96 hours, regardless of the initial score, the mortality rate was at least 50% when the score increased, 27% to 35% when it remained unchanged, and less than 27% when it decreased. Differences in mortality were better predicted in the first 48 hours than in the subsequent 48 hours. There was no significant difference in the length of stay among these groups. Except for initial scores of more than 11 (mortality rate >90%), a decreasing score during the first 48 hours was associated with a mortality rate of less than 6%, while an unchanged or increasing score was associated with a mortality rate of 37% when the initial score was 2 to 7 and 60% when the initial score was 8 to 11.Conclusions Sequential assessment of organ dysfunction during the first few days of ICU admission is a good indicator of prognosis. Both the mean and highest SOFA scores are particularly useful predictors of outcome. Independent of the initial score, an increase in SOFA score during the first 48 hours in the ICU predicts a mortality rate of at least 50%.
Article
OBJECTIVE: To determine the effectiveness of early, routine antioxidant supplementation using α-tocopherol and ascorbic acid in reducing the rate of pulmonary morbidity and organ dysfunction in critically ill surgical patients. SUMMARY BACKGROUND DATA: Oxidative stress has been associated with the development of the acute respiratory distress syndrome (ARDS) and organ failure through direct tissue injury and activation of genes integral to the inflammatory response. In addition, depletion of endogenous antioxidants has been associated with an increased risk of nosocomial infections. The authors postulated that antioxidant supplementation in critically ill surgical patients may reduce the incidence of ARDS, pneumonia, and organ dysfunction. METHODS: This randomized, prospective study was conducted to compare outcomes in patients receiving antioxidant supplementation (α-tocopherol and ascorbate) vs those receiving standard care. The primary endpoint for analysis was pulmonary morbidity (a composite measure of ARDS and nosocomial pneumonia). Secondary endpoints included the development of multiple-organ failure, duration of mechanical ventilation, length of ICU stay, and mortality. RESULTS: Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60 to 1.1) in patients receiving antioxidant supplementation. Multiple-organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19 to 0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay. CONCLUSIONS: The early administration of antioxidant supplementation using α-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients.