Review of Phase I Safety Trial of Intravenous Ascorbic Acid in Patients With Severe Sepsis

• Journal Listing
• J Transl Med
• v.12; 2014
• PMC3937164

J Transl Med. 2014; 12: 32.

Phase I safety trial of intravenous ascorbic acrid in patients with astringent sepsis

Alpha A Fowler, III, ¹ Aamer A Syed,¹ Shelley Knowlson,² Robin Sculthorpe,^three Don Farthing,^four Christine DeWilde,¹ Christine A Farthing,^four Terri 50 Larus,⁴ Erika Martin,⁵ Donald F Brophy,⁵ and Seema Gupta⁶, Medical Respiratory Intensive Care Unit Nursing

Alpha A Fowler, Three

¹Division of Pulmonary Disease and Critical Intendance Medicine, Section of Internal Medicine, School of Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 23298-0050, USA

Aamer A Syed

¹Division of Pulmonary Illness and Critical Care Medicine, Section of Internal Medicine, School of Medicine, Virginia Republic Academy, PO Box 980050, Richmond, VA 23298-0050, USA

Shelley Knowlson

ⁱⁱDepartment of Disquisitional Intendance Nursing, Virginia Commonwealth University Wellness Organization, Richmond, Virginia, USA

Robin Sculthorpe

³Investigational Drug Services, Department of Chemist's Services, School of Pharmacy, Virginia Democracy University, Richmond, Virginia, United states of america

Don Farthing

^fourPartition of Nephrology, Section of Internal Medicine, School of Medicine, Virginia Democracy Academy, Richmond, Virginia, USA

Christine DeWilde

¹Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Schoolhouse of Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 23298-0050, USA

Christine A Farthing

⁴Division of Nephrology, Section of Internal Medicine, School of Medicine, Virginia Republic University, Richmond, Virginia, USA

Terri Fifty Larus

⁴Division of Nephrology, Department of Internal Medicine, Schoolhouse of Medicine, Virginia Commonwealth Academy, Richmond, Virginia, United states

Erika Martin

^fiveDepartment of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth Academy, Richmond, Virginia, Usa

Donald F Brophy

⁵Department of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Republic University, Richmond, Virginia, United states of america

Seema Gupta

⁶Health Diagnostic Laboratory, Richmond, Virginia, Us

Bernard J Fisher¹ and Ramesh Natarajan¹

^onePartition of Pulmonary Disease and Critical Intendance Medicine, Department of Internal Medicine, School of Medicine, Virginia Republic University, PO Box 980050, Richmond, VA 23298-0050, USA

^twoDepartment of Critical Care Nursing, Virginia Democracy University Wellness System, Richmond, Virginia, United states

^threeInvestigational Drug Services, Section of Chemist's Services, Schoolhouse of Pharmacy, Virginia Commonwealth Academy, Richmond, Virginia, United states of america

⁴Division of Nephrology, Section of Internal Medicine, School of Medicine, Virginia Democracy Academy, Richmond, Virginia, USA

^vDepartment of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, U.s.a.

⁶Health Diagnostic Laboratory, Richmond, Virginia, United states

Bernard J Fisher

¹Division of Pulmonary Disease and Critical Care Medicine, Section of Internal Medicine, Schoolhouse of Medicine, Virginia Democracy University, PO Box 980050, Richmond, VA 23298-0050, U.s.

Ramesh Natarajan

ⁱDivision of Pulmonary Affliction and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 23298-0050, USA

Received 2013 Nov 12; Accepted 2014 January 2.

Supplementary Materials

Additional file one Patient Flow Diagram. Catamenia diagram of the progress through the phases of the safe trial (enrollment, allocation, follow-up, and analysis).

GUID: AC551A1F-91C2-47D7-A775-0CFB754EFBCC

Additional file two: Table S1 Secondary outcomes of septic patients treated or not treated with intravenous ascorbic acrid. Includes days on vasopressor, ventilator free days, ICU length of stay, and 28-twenty-four hours mortality.

GUID: C2E4177C-A408-4F3B-A57E-0237AA427E35

Additional file 3: Table S2 Components of the Sequential Organ Failure Assessment (SOFA) scoring system. Describes the clinical parameters of the scoring organization.

GUID: EADE7470-437B-4C9E-8CC6-890289C7CD1B

Abstruse

Background

Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental fauna models. The objective of this randomized, double-blind, placebo-controlled, stage I trial was to determine the prophylactic 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 i:one:ane to receive intravenous infusions every half dozen hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = eight), or Hi-AscA (200 mg/kg/24 h, northward = 8), or Placebo (5% dextrose/water, n = eight). The primary finish points were ascorbic acid condom and tolerability, assessed every bit treatment-related adverse-issue frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or airsickness. 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 unabridged cohort were 17.9 ± 2.4 μM (normal range 50-seventy μM). Ascorbic acid infusion speedily and significantly increased plasma ascorbic acid levels. No agin safety events were observed in ascorbic acrid-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 poly peptide and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no meaning ascent, suggesting attenuation of vascular endothelial injury.

Conclusions

Intravenous ascorbic acrid infusion was safety and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.

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 ascent in Intensive Care Units worldwide with studies from multiple countries showing that organ failure contributes cumulatively to patient mortality [1-3]. Patients with astringent sepsis suffer higher mortality rates compared to patients with organ failure but no sepsis. Despite over 15,000 patients studied and over i billion dollars in study costs constructive sepsis therapy remains elusive [4,five]. Clinical trials that have targeted mediators of inflammation or coagulation such every bit atorvastatin [6] or activated protein C [7] have not reduced septic mortality, suggesting that unmarried-target therapy fails to meet the challenges of circuitous 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 acrid infusion improved capillary claret catamenia, microvascular barrier function, and arteriolar responsiveness to vasoconstrictors in septic animals [8,9]. Recently, we showed that parenterally infusing ascorbic acid at a concentration of 200 mg/kg attenuated vascular lung injury in septic mice by multiple mechanisms, including attenuation of the proinflammatory mediators, enhanced alveolar epithelial bulwark function, increased alveolar fluid clearance, and prevention of sepsis-induced coagulopathy [ten,11]. In addition, ascorbic acid scarce mice were found to be more susceptible to sepsis-induced multiple organ dysfunction and parenteral infusion of ascorbic acrid 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 direct with survival [13]. Ascorbic acid depletion in sepsis results from: i) ascorbic acid consumption by reduction of plasma free fe, ii) ascorbic acrid consumption past the scavenging of aqueous free radicals, and three) by destruction of the oxidized form of ascorbic acid, dehydroascorbic acid [fourteen]. Dosing and bio-distribution information in humans show that pharmacological concentrations of ascorbic acrid can only be attained post-obit intravenous assistants [15]. Surprisingly, few studies in critically ill patients infusing ascorbic acrid take been performed. Nathens and colleagues infused ascorbic acid at 1 gram every eight hours combined with oral vitamin E for 28 days in 594 surgically critically ill patients and institute a significantly lower incidence of astute lung injury and multiple organ failure [16]. Tanaka et al. infused ascorbic acrid continuously at 66 mg/kg/hour for the showtime 24 hours in patients with greater than l% surface area burns and showed significantly 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 antioxidants (tocopherol, N-acetyl-cysteine, selenium), in patients with established ARDS showed a fifty% reduction in mortality [xviii]. 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 decide whether intravenous ascorbic acrid was rubber 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 equally a marker of vascular injury [xix-21]. The work reported in this study has previously been presented at the American Thoracic Society International Meeting [22].

Methods

This written report 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 rubber monitoring lath oversaw the trial.

Patient enrollment

Patients were screened and enrolled post-obit admission to the Medical Respiratory Intensive Care Unit in the VCU Medical Center, Richmond, Virginia. Severe sepsis was defined as: ane) Presence of a systemic inflammatory response: (fever: >38°C or hypothermia: <36°C (core temp just), heart rate > 90 beats/min, leukocytosis: >12,000 WBC/μL or leukopenia: <iv,000 WBC/μL or >10% ring forms) [23], 2) Suspected or proven infection, and 3) Presence of sepsis-induced organ dysfunction: Arterial hypoxemia (P_aO₂/F_iO₂ < 300), systolic blood pressure (SBP) < 90 mm Hg or SBP decrease > xl 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 > two mg/dL. If these iii criteria were met within 48 hours of ICU access, informed consent was obtained from family members of patients deemed eligible for the study. Study groups in this trial were 1) Placebo: five% dextrose and water; 2) Low dose ascorbic acid (Lo-AscA): 50 mg/kg/24 hours; or three) High dose ascorbic acid (Hi-AscA): 200 mg/kg/24 hours. Ascorbic acid dosage was divided into 4 equal doses and administered over thirty minutes every half dozen hours for 96 hours in 50 ml of 5% dextrose and h2o. Study drug infusion was initiated 2 to four hours following informed consent and randomization.

The study blind was established and maintained by the VCU Investigational Pharmacy Section 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/twenty-four hours) in a 1:1:ane 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 Acrid Injection, USP, (Bioniche Pharma, Lake Forest, IL) was used. Ascorbic acid or placebo solutions were prepared in matching volumes with amber shrouding for calorie-free protection and to preserve the blind. Air was removed from Iv bags for protection against ascorbic acid oxidation. Ascorbic acid was stored at 2–8°C for upwards to 24 hours prior to utilize. Preliminary experiments showed no oxidation under these brief storage conditions.

Study information management

Collected data was managed using REDCap (Inquiry Electronic Data Capture), a secure, web-based data drove and storage tool hosted at VCU [25].

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 information 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 iv-day study period) [28,29].

Study drug infusion and condom monitoring

Vital signs were monitored every v minutes during infusion and every 5 minutes for 45 minutes later 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 acrid infusion: 1) Hypotension: Divers as a fall in hateful arterial blood pressure of 20 mm Hg during or following infusion, two) Tachycardia: Defined equally an increase in heart rate of twenty beats per minute during or post-obit infusion, three) Hypernatremia: Standard of care utilizes 0.9% saline for volume resuscitation. L-Ascorbic acid preparation used for this study presented a minor sodium load, therefore a potential for hypernatremia to develop existed and 4) Nausea or airsickness: were monitored both during and after ascorbic acrid administration past investigators and by MRICU nursing staff. If one of the adverse events listed above was observed, ICU nursing was equipped with bedside algorithms designed to manage the adverse upshot. If an upshot was observed, drug infusion was halted. If the consequence 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 four days. Patients were then followed clinically for 28 days.

Blood samples

Whole venous blood was fatigued into sterile Vacutainer® tubes (Becton, Dickinson & Co., Franklin Lakes, NJ): serum tube (BD 367812, blood-red top, clot activator) and plasma tube (lavender top, BD 367861, K2EDTA). Serum samples were immune to coalesce for 60 min at room temperature. Plasma and serum were separated past centrifugation. An aliquot of freshly isolated plasma was processed for ascorbic acid analysis. Remaining plasma and serum were aliquoted and frozen at -lxx°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 (ten,000 g, 10 min, 4°C). Supernatants were aliquoted and frozen at -seventy°C for batch assay. Quality control samples consisted of normal plasma spiked with ascorbic acid (100 & 1,000 μM), candy in the same manner, and stored with patient samples. Plasma Ascorbic Acrid 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 acrid dosing. Concentrations were measured using high force per unit area liquid chromatography (HPLC) with UV detection. Chromatography was performed on an Onyx Monolithic C18 Cavalcade (100 × 4.6 mm; Phenomenex, Torrance, CA) with a mobile phase using a slope 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 summit expanse analysis and external standardization. Ascorbic acid standards (0–1,000 μM) were freshly prepared and treated in the aforementioned way as the exam plasma samples.

Biomarkers

Biomarkers measured for this written report were identified prior to the start of the study. C-Reactive Protein (CRP): A loftier 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 (Percentage): Procalcitonin levels were quantified using a sandwich ELISA kit according to manufacturer's instructions (RayBiotech, Inc., Norcross, GA). Thrombomodulin (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 monoclonal antibiotic specific for human thrombomodulin.

Meet Additional file 1 for description of methods utilized for biomarker analysis.

Statistical assay

All analyses in this study were pre-specified. Statistical analysis was performed using SAS 9.3 and Graphpad PRISM half-dozen.0. The results are expressed as means ± SE. Differences between and inside groups were analyzed using two-factor analysis of variance with Tukey's studentized range exam. Summary information 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 (modify in daily total SOFA score compared with 24-hour interval 0) over 4 study days by comparing the regression coefficients using Educatee'south t-test [28,29].

Results

Enrolled written report patients

Over a 1 year period, 35 patients were screened and 26 patients were enrolled. Reasons for excluding the 9 patients are equally follows: a) iii patients had terminal cancer and were non 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 iv patients. Eight were enrolled in the placebo group, 8 enrolled in the Lo-AscA group, and 10 enrolled in the Hello-AscA. One patient in the Hi-AscA grouping was withdrawn past family members and transferred to another institution. Ane other How-do-you-do-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. Table1 shows the demographics of enrolled patients. The APACHE Ii and SOFA scores betwixt groups were statistically identical. Table2 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 astute kidney injury or respiratory failure was present. Secondary outcomes (i.e., days on vasopressor, Ventilator days, ICU length of stay and 28 solar day mortality) are now reported in Boosted file 2: Tabular array S1. The cohort of patients in this trial had a high incidence of respiratory failure. Xix patients had ARDS at entry as defined by the Berlin Definition with P_aO₂/F_iO₂ (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 2 were not intubated for ventilatory support. One patient in the group with PF ratios higher up 300 eventually fell below 300 and satisfied the Berlin Definition of ARDS.

Table one

Baseline demographic data of septic patients treated or non treated with intravenous ascorbic acid

Handling	Gender	Age	APACHE 2 score a	SOFA score b
Placebo	4 male iv female	54 – 68 years	20.4 (fifteen – 29)	13.3 ± 2.ix
Lo-AscA	5 male person 3 female	30 – lxx years	xx.4 (12 – 23)	x.1 ± 2.0
Hi-AscA	4 male 4 female	49 – 92 years	24.0 (12 – 33)	10.8 ± 4.iv

Table 2

Clinical data on patients with astringent sepsis

Underlying conditions	Source of sepsis	Organism	Renal failure?	Respiratory failure?
Lung cancer	Pneumonia	Blood: Eastward.coli, Strep bovis	no	yes
		Resp: Eastward.coli
Prodrome with nausea and airsickness for 7 days	Pneumonia	Blood: culture negative	no	yes
		Urine: Legionella antigen positive
ETOH cirrhosis	Spontaneous bacterial peritonitis	Blood: culture negative	no	yes
Condition/Post gastric bypass	Urinary tract infection	Blood: East. Coli	no	yeah
Obstructive nephrolithiasis pyelonephritis	Urinary tract infection	Blood: Eastward.Coli	no	yes
		Urine: E.Coli
End stage renal disease	Catheter sepsis	Blood: MRSA	aye (prior to admission)	yeah
Acute myelogenous leukemia (relapse)	Portacath sepsis	Blood: MRSA	no	yes
		Urine: Enterobacter
Influenza	Pneumonia with coexistent Influenza A	Blood: Strep pneumonia	no	yes
		Resp: Flu A
Diabetes mellitus	Infected diabetic pes ulcer	Blood: Staph aureus	no	yes
Chronic kidney disease		Torso Fluid: Staph aureus
Gout		Resp: MRSA
Head and neck cancer	Pneumonia	Claret: culture negative	no	yes
		Resp: culture negative
Diabetes mellitus	Pneumonia and colitis	Blood: culture negative	yeah (dialysis required)	yep
Congestive center failure
Gastrointestinal hemorrhage
		Resp: MRSA
Cellulitis	Pneumonia	Blood: Group a strep.	no	no
Hypercholesterolemia	Urinary tract infection
Multiple myeloma	PneumoniaUrinary tract infection	Claret: Gram positive cocci	no	yep
		Urine: Proteus mirabilis
Non-Hodgkins lymphoma	Pancreatitis	Resp: Aspergillus fumigatus	no	yes
Bone marrow transplant	Intra-intestinal sepsis	Claret: Gram negative rods, Gram positive cocci	no	yes
Bowel perforation
Mail allogeneic os marrow transplant	Pneumonia	Blood: culture negative	no	yes
Chronic opiate use	Aspiration pneumonia	Blood: Strep. pneumonia	no	yes
Constitute obtunded		Resp: Strep. pneumonia, Candida glabrata
Diabetes mellitus	Aspiration pneumonia	Resp: Gram negative rods, gram positive cocci	yes (prior to admission)	yeah
End phase renal illness
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	Claret: culture negative	no	no
Hepatorenal syndrome
Chronic obstructive pulmonary illness	Pneumonia	Blood: Gram positive rods	no	yes
Astringent ankylosing spondylitis	Urinary tract infection	Claret: Klebsiella pneumonia	no	yes
		Urine: Klebsiella pneumonia
Severe aortic stenosis
Hepatitis C cirrhosis	Health care caused pneumonia	Blood: culture negative	yes (dialysis required)	yes
		Urine: Enterococcus
Esophageal varicies
Systemic mastocytosis	Pneumonia	Claret: culture negative	no	yes
Congestive heart failure		Resp: Budding yeast with pseudohyphae

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.east., hypotension, tachycardia, hypernatremia, or nausea/airsickness). Infusions were halted in i septic patient (Hullo-AscA) post-obit infusion #14 (84 hours) for a ventricular arrhythmia after determined by Cardiology consultants to be electrical artifact. This patient is included in the analysis.

Plasma ascorbic acrid levels

Plasma ascorbic acid levels in all septic patients at enrollment were subnormal (i.due east., hyposcorbic) at 17.9 ± two.4 μM (normal 50 – lxx μM) and were not significantly different at baseline (Effigyi). Ascorbic acid levels in the placebo group roughshod from 20.ii (11–45) μM at entry to 15.6 (vii–27) μM on study day 4. Ascorbic acid levels increased 20-fold in the low dose treatment group from xvi.vii (xiv–28) μM at baseline to 331 (110–806) μm on mean solar day 4. Ascorbic acid levels increased dramatically in Hi-AscA patients from 17.0 (11–50) μM at baseline to 3,082 (one,592 - 5,722) μm on twenty-four hours four. Thus, ascorbic acid levels rose quickly in the two treatment groups and were significantly higher than placebo within twelve hours (Lo-AscA vs. placebo p < 0.005, How-do-you-do-AscA vs. placebo p < 0.0005) remaining consistently elevated for the 96-hour infusion flow. Furthermore, ascorbic acid levels in the Hello-AscA grouping were significantly college (p < 0.005) than the Lo-AscA grouping from the 12 hr bespeak forrard reaching millimolar concentrations. These data ostend "hyposcorbic" levels nowadays in untreated human sepsis and show that intermittent ascorbic acrid infusion every half-dozen hours produces sustained steady-state plasma levels.

Plasma ascorbic acid levels following intravenous infusion of ascorbic acrid. Plasma ascorbic acid levels were subnormal at entry (<fifty μM, dotted line). Ascorbic acid levels rose speedily in the 2 treatment groups and were significantly college than placebo within twelve hours (Lo-AscA vs. placebo p < 0.005, How-do-you-do-AscA vs. placebo p < 0.0005) remaining consistently elevated for 96 hours. Ascorbic acid levels in the How-do-you-do-AscA group were significantly higher than the Lo-AscA group from the 12 hour point forrad. These data evidence that an intermittent ascorbic acid infusion protocol (every 6 hours) produces sustained steady country levels in patients with severe sepsis. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Impact of ascorbic acid infusion on organ failure

SOFA scores at enrollment were: Placebo – 13.3 ± ii.nine, Lo-AscA – 10.1 ± ii.0, and Hi-AscA x.eight ± 4.4 and were non significantly different beyond groups. The components of the SOFA score are listed in Boosted file 3: Tabular array S2. Post-obit normalization of the daily SOFA scores, patients treated with either dose of ascorbic acrid exhibited descending SOFA scores over the 4-twenty-four hours study catamenia (p < 0.05, slopes significantly non-zero). High dose ascorbic acid patients exhibited significantly faster declines in the regression slopes of delta daily total SOFA scores over time compared to placebo (-0.043 vs. 0.003, p < 0.01) (Figure2). Placebo patients exhibited a gradual ascension in SOFA scores. Though the cohort size is express, these data advise that ascorbic acid infusion significantly attenuates the systemic organ injury associated with sepsis.

Upshot of ascorbic acid infusion on Sequential Organ Failure Assessment (SOFA) score (days 0–iv). 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 (Howdy-AscA vs. placebo p < 0.01). Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Impact of ascorbic acid infusion on biomarkers

Serum/plasma obtained from enrolled subjects were analyzed for three biomarkers: C-reactive protein (CRP), procalcitonin (Per centum), and thrombomodulin (TM). CRP and PCT were quantified as surrogates for inflammation while TM was employed every bit a surrogate for endothelial injury. At enrollment, biomarker levels beyond the three groups were not significantly different. Serum CRP trended slowly down over the 96 hour menses in the placebo group. Patients receiving ascorbic acrid exhibited rapid reductions in CRP levels achieving significantly lower levels when compared to their own baseline and placebo by 24 hours (FigurethreeA, p < 0.05). Percent levels trended college in placebo-infused patients 24 hours following the onset of sepsis though not reaching statistical significance. Serum PCT levels in patients receiving loftier dose ascorbic acid declined, becoming significantly lower than baseline by 48 hours (Figure3B, p < 0.05). PCT in patients receiving high dose ascorbic acid connected 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 tendency upwards across 36 hours, remaining elevated when compared to ascorbic acid treated patients though the values were not statistically meaning (Figure4). Importantly ascorbic acrid treated patients did not exhibit the upward trend in TM levels observed in placebo-infused patients. These results suggest that ascorbic acrid infusion produces early reductions in proinflammatory mediators in patients with astringent sepsis. The results further suggest that ascorbic acid infusion attenuates the evolution of endothelial injury feature of astringent sepsis in humans.

Serum C-reactive poly peptide (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 equally 24 hours. Ascorbic acid infusion reduced CRP levels in both groups throughout the 4 study days (#p < 0.05 vs 0 hour). CRP levels in placebo patients slowly fell over the class of the iv day study catamenia. (B) Patients in the Lo-AscA and How-do-you-do-AscA groups exhibited reduced serum PCT levels beginning at 12 hours. Patients in the Hi-VitC grouping exhibited farther pregnant 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 mail service onset of sepsis. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Plasma thrombomodulin (TM) levels measured in septic placebo controls and ascorbic acid infused patients. Plasma TM levels measured in the ascorbic acrid infused patients exhibited no rise throughout the 4 days of study. Patients in the placebo group showed a tendency towards increased plasma TM levels start at 36 hours, though it did not accomplish statistical significance. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Discussion

This phase I trial focused on the rubber of administering intravenous ascorbic acid to patients with astringent sepsis. The intravenous road of assistants was called in this trial in order to achieve high ascorbic acid plasma levels. Padayatty and colleagues showed that loftier-level ascorbic acid plasma concentrations could only exist achieved past intravenous administration [15]. Prior human studies employing pharmacologic ascorbic acrid dosing report no adverse events. Nathens et al. administered 1 gram of ascorbic acrid every 8 hours for 28 days to surgically critically ill patients with no ill effects [16]. Tanaka et al. administered 66 mg/kg/hour for 24 hours to patients with l% surface expanse burns with no adverse events [17]. Hoffer et al. intravenously administered upwards to 90 grams of ascorbic acrid three times weekly to patients with advanced malignancy with no agin 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 handling artillery of this study suffered whatsoever identifiable adverse consequence. Every bit noted higher up, 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 handling strategy in critically ill patients with severe sepsis appears to be safe.

Prior studies bear witness that patients with astringent sepsis showroom significantly reduced plasma ascorbic acid levels upon admission to intensive intendance [31]. The hateful 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 l – lxx μM (Figureane). Prior studies [13,14,26], and the electric 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 iv-day study menstruum despite receiving full ICU standard of care practice for severe sepsis (Figure1). Ascorbic acid depletion in sepsis results from ascorbic acid consumption past the reduction of plasma gratuitous iron, ascorbic acid consumption by the scavenging of aqueous gratis radicals (peroxyl radicals), and by the devastation of the oxidized course of ascorbic acid dehydroascorbic acid[xiv]. Sepsis farther inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion. Sepsis-induced ascorbic acid destruction permits uncontrolled oxidant activity which amplifies tissue injury [fourteen,32,33]. Ascorbic acrid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every vi hours administration protocol (Effigy1).

SOFA scores are robust indicators of mortality during critical illness. SOFA score increases during the get-go 48 hours of ICU intendance predict a mortality charge per unit of at least fifty% [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 access were subnormal (17.9 ± 2.4 μM), a mean initial SOFA score of 11.four ± 3 in patients with severe sepsis was not surprising. This study is in understanding with other studies which show that plasma ascorbic acid levels in astringent 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 remarkable in patients receiving the high dose ascorbic acrid infusion (Effigytwo).

C-reactive protein (CRP) [19] and procalcitonin (Per centum) [xx] 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 sick. CRP in circulation has a curt half-life of approximately 19 hours. Thus, the kinetics of CRP make information technology a useful monitor for tracking the inflammatory response produced by infection, and the response to antibody treatment. Lobo et al. reported that patients with CRP levels greater than x mg/dL at ICU admission exhibited significantly college rates of multiple organ failure likewise every bit college mortality rates [34]. A decrease in CRP levels in Lobo's report after 48 hours was associated with a mortality charge per unit 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 acrid infusion in this trial promptly reduced serum CRP levels in septic patients (Figure3A). Thus, the findings in this study support the findings of Lobo et al. with descending CRP levels beingness associated with lower mortality rate and reduced levels or organ failure. Jensen and colleagues found that loftier maximal procalcitonin levels were an early contained predictor of all-cause mortality in a 90-solar day follow-up period after intensive care unit access [20]. Karlsson and colleagues [21] showed that bloodshed in patients with severe sepsis was lower in those patients in whom procalcitonin concentrations roughshod by more than 50% at 72 hours with respect to initial values. Infusion of ascorbic acid into patients with astringent sepsis in this study reduced serum procalcitonin levels past greater than 50% (Figure3B). Thrombomodulin is an endothelial cell leap molecule that captures thrombin property it adjacent to protein C bound to its receptor (endothelial protein C receptor). Elevated soluble TM in the circulation indicates endothelial jail 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 written report, thrombomodulin levels in patients randomized to placebo began to rise at approximately 36 hours into the report period, indicating sepsis-induced endothelial injury (Effigy4). 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 suggest that intravenous ascorbic acrid acts to attenuate the proinflammatory land of sepsis and perhaps attenuates the evolution of endothelial injury.

On the ground of this study and our prior preclinical studies, nosotros speculate as to the pleiotropic mechanisms by which ascorbic acrid would be beneficial in sepsis. Ascorbic acid is rapidly taken upward by endothelial cells in millimolar quantities where it scavenges reactive oxygen species and increases endothelial nitric oxide synthase-derived nitric oxide past restoring tetrahydrobiopterin content, thus, increasing bioavailable nitric oxide. Equally we and others accept shown in bones investigations [10,11,37], by inhibiting NFκB activation, ascorbic acid could potentially attenuate the "cytokine storm" that arises due to NFκB driven genes known to exist activated in sepsis. Septic ascorbic acid-scarce neutrophils fail to undergo normal apoptosis. 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 acrid levels. Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging 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 annually due to severe sepsis [ane,38-40]. Multiple treatment trials have failed to measurably improve outcomes. The bulk of trials have singly eliminated certain proinflammatory mediators which inquiry has suggested promotes tissue damage. The single mediator arroyo 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 stage I trial shows that ambitious repletion of plasma ascorbic acid levels in patients with astringent sepsis is safe. This early on work in septic patients suggests that pharmacologic ascorbic acid repletion reduces the extent of multiple organ failure and attenuates circulating injury biomarker levels.

Abbreviations

AscA: Ascorbic acrid; CRP: C-reactive protein; PCT: Procalcitonin; SOFA: Sequential organ failure cess; TM: Thrombomodulin.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

AAF, RN, BJF, AAS: Hypothesis/delineation. AAF, AAS, DF, RS, SK, CD: Report 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 commodity. AAF, RN, AAS, and BJF conceived, designed, or planned the study, interpreted the results, and wrote sections of the initial typhoon. DF, CAF, and TLL designed, validated and performed the plasma ascorbic acid HPLC analysis. SK, CD aided in study design and data drove. RS helped blueprint the study and wrote sections of the initial typhoon. 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.

Supplementary Cloth

Additional file 1:

Patient Catamenia Diagram. Flow diagram of the progress through the phases of the condom trial (enrollment, allocation, follow-upward, and analysis).

Boosted file 2: Table S1:

Secondary outcomes of septic patients treated or not treated with intravenous ascorbic acrid. Includes days on vasopressor, ventilator free days, ICU length of stay, and 28-twenty-four hour period mortality.

Boosted file 3: Table S2:

Components of the Sequential Organ Failure Assessment (SOFA) scoring system. Describes the clinical parameters of the scoring organisation.

Acknowledgement

The authors wish to acknowledge back up for this phase I trial from: 1) The Aubrey Sage Macfarlane Astute Lung Injury Fund, 2) VCU Clinical and Translational Science Award UL1TR000058 from the National Center for Advancing Translational Sciences, three) VCU Investigational Pharmacy Services, 4) The Jeffress Memorial Trust, and five) The Advertizement Williams Trust.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937164/

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