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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Multiple Organ Failure, Sepsis, Systemic Inflammatory Response Syndrome, Trauma

Intervention / Treatment
-----------------
* Drug: Ascorbic Acid


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4x 1 gram bolus (q12H) dosage regimen<br>1 gram of intravenous Vitamin C (ascorbic acid) is given 4 times at 12 hour intervals (total dose 4 grams). | Drug: Ascorbic Acid<br>* 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.<br>* Other names: Vitamin C;|
| Experimental: 4x 5 grams bolus (q12H) dosage regimen<br>5 grams of intravenous Vitamin C (ascorbic acid) is given 4 times at 12 hour intervals (total dose 20 grams). | Drug: Ascorbic Acid<br>* 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.<br>* Other names: Vitamin C;|
| Experimental: 4 gram continuous dosage regimen<br>1 gram per 12 hours of intravenous Vitamin C (ascorbic acid) is given continuously for 48 hours | Drug: Ascorbic Acid<br>* 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.<br>* Other names: Vitamin C;|
| Experimental: 20 gram continuous dosage regimen<br>5 gram per 12 hours of intravenous Vitamin C (ascorbic acid) is given continuously for 48 hours | Drug: Ascorbic Acid<br>* 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.<br>* Other names: Vitamin C;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Critical Care