Pharmacokinetics of Two Different High-dose Regimens of Intravenous Vitamin C in Critically Ill Patients

The purpose of this study is to determine the pharmacokinetic properties of two different dosage regimens of intravenous vitamin C in patients admitted to the Intensive Care Unit with life-threatening illness.

Study Overview

• Status: Completed
• Conditions: Sepsis; Systemic Inflammatory Response Syndrome; Trauma; Multiple Organ Failure
• Intervention / Treatment: Drug: Ascorbic Acid

Detailed Description

Rationale:

Critically ill patients with trauma or sepsis exhibit a high degree of vitamin C deficiency at ICU admission and vitamin C plasma concentrations decrease even more during the first three days of admission. Vitamin C is a natural anti-oxidant and crucial for endothelial and organ protection

Objective:

To determine the pharmacokinetics of two high dose regimens of intravenous vitamin C in critically ill patients, in particular the attained plasma concentration and the fraction retained in the body and excreted in urine.

Study design:

Prospective randomized controlled pharmacokinetic intervention study

Study population:

Adult critically ill patients admitted to the ICU of the VU University Medical Center, Amsterdam, with sepsis or SIRS after major surgery or trauma with a non-neurological sequential organ failure (SOFA) score >6 and an expected length of ICU stay of >96 hours.

Intervention (if applicable):

Patients will receive either 2 or 10 gram/day vitamin C intravenously twice daily for two days in bolus or continuous infusion.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sepsis or Systemic Inflammatory Response Syndrome (SIRS) after major surgery or trauma;
• Non-neurological sequential organ failure assessment (SOFA) score >6;
• Expected length of ICU stay > 96 hours;
• Written proxy consent by legal representative.

Exclusion Criteria:

• Admission after out of hospital cardiac arrest
• Prior use of supplemental vitamin C in the week before
• Major bleeding
• Pre-existent renal insufficiency defined as an eGFR of < 30 ml/min/1.73 m2 (stadium 4-5)
• Expected need for renal replacement therapy within 48 hours
• Known glucose 6-phosphate dehydrogenase deficiency
• History of urolithiasis or oxalate nephropathy
• Previous use of prolonged high dose vitamin C supplements
• Hemochromatosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4x 1 gram bolus (q12H) dosage regimen; 1 gram of intravenous Vitamin C (ascorbic acid) is given 4 times at 12 hour intervals (total dose 4 grams).	Drug: Ascorbic Acid; Patients receive vitamin C 4 times in either high (5g) or moderate (1g) dose. Vitamin C will be administered intravenously (ascorbinezuur CF 100 mg/ml, Centrafarm BV, Etten Leur, Netherlands) in 50ml of NaCl 0.9%, infused over 30 minutes.; Other Names: Vitamin C
Experimental: 4x 5 grams bolus (q12H) dosage regimen; 5 grams of intravenous Vitamin C (ascorbic acid) is given 4 times at 12 hour intervals (total dose 20 grams).	Drug: Ascorbic Acid; Patients receive vitamin C 4 times in either high (5g) or moderate (1g) dose. Vitamin C will be administered intravenously (ascorbinezuur CF 100 mg/ml, Centrafarm BV, Etten Leur, Netherlands) in 50ml of NaCl 0.9%, infused over 30 minutes.; Other Names: Vitamin C
Experimental: 4 gram continuous dosage regimen; 1 gram per 12 hours of intravenous Vitamin C (ascorbic acid) is given continuously for 48 hours	Drug: Ascorbic Acid; Patients receive vitamin C 4 times in either high (5g) or moderate (1g) dose. Vitamin C will be administered intravenously (ascorbinezuur CF 100 mg/ml, Centrafarm BV, Etten Leur, Netherlands) in 50ml of NaCl 0.9%, infused over 30 minutes.; Other Names: Vitamin C
Experimental: 20 gram continuous dosage regimen; 5 gram per 12 hours of intravenous Vitamin C (ascorbic acid) is given continuously for 48 hours	Drug: Ascorbic Acid; Patients receive vitamin C 4 times in either high (5g) or moderate (1g) dose. Vitamin C will be administered intravenously (ascorbinezuur CF 100 mg/ml, Centrafarm BV, Etten Leur, Netherlands) in 50ml of NaCl 0.9%, infused over 30 minutes.; Other Names: Vitamin C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Vitamin C plasma concentration	Baseline (before intervention), thereafter at 1, 2, 4, 8, 12, 24, 36, 48, 72, 96 hours after first intervention
Vitamin C excreted in urine	0-12hours after first intervention; 36-48 hours after first intervention

Secondary Outcome Measures

Outcome Measure	Time Frame
Oxalate excretion in urine	0-12hours after first intervention; 36-48 hours after first intervention
F2-isoprostanes (oxidative damage biomarker)	0, 24 and 72 hours after first intervention
CellROX (reactive oxygen species activity in leukocytes)	0 and 24 hours after first intervention
Vasopressor requirements (noradrenalin dose)	0, 12, 24, 48, 72 and 96 hours after first intervention
Renal resistive index (ultrasonography)	0, 4, 24, 72 hours after first intervention
Serum creatinine and creatinine clearance	0, 24, 48, 72, 95 after first intervention
Sequential Organ Failure Assessment (SOFA) score	0, 24, 48, 72, 95 after first intervention

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: H.M. Oudemans-van Straaten, MD, PhD, Amsterdam Umc, Location Vumc

Publications and helpful links

General Publications

• de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, Spoelstra-de Man AME, Girbes AR, Swart EL, Oudemans-van Straaten HM. Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens. Chest. 2018 Jun;153(6):1368-1377. doi: 10.1016/j.chest.2018.02.025. Epub 2018 Mar 6.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: May 21, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (Estimate): May 27, 2015

Study Record Updates

• Last Update Posted (Actual): August 2, 2017
• Last Update Submitted That Met QC Criteria: August 1, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Critical Care
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Shock; Systemic Inflammatory Response Syndrome; Multiple Organ Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: NL50578.029.14; 2014-003680-38 (EudraCT Number)